dental implants.pdf

Histometric Analysis of Bone Repair in Bone-ImplantInterface Using a Polylactic/Polyglycolic Acid CopolymerAssociated With Implants in Rabbit TibiaAlexandre Rodrigues Freire, MSc1*

Ana Claudia Rossi, DDS1

Thallita Pereira Queiroz, PhD2

Jessica Lemos Gulinelli, PhD2

Francisley Avila Souza, PhD2

Rogerio Margonar, PhD3

Idelmo Rangel Garcia-Junior, PhD2

Eduardo Hochuli-Vieira, PhD4

Roberta Okamoto, PhD5

The purpose of this study was to evaluate the association of the combination of polylactic/polyglycolic acid

around implants installed with and without primary stability through the histometric analysis of bone-implant

interface. We used male rabbits, each of which received 2 titanium implants in each tibial metaphysis. The

animals were divided into 4 groups: control with primary stability (CPS), control without primary stability (C),

polymer with primary stability (PPS), and polymer without primary stability (P). Euthanasia was performed at

postoperative days 40 and 90. The pieces were embedded in resin, sectioned, scraped, and stained with alizarin

red and Stevenel blue. Histometric analysis evaluated the linear extension of contact between the bone and

implant surface on the implant collar (CIC) and contact between the bone and implant surface on the first

thread (CFT). Also evaluated was the area of newly formed bone (ANB) in the first thread. The results showed

that there was new bone formation in all groups and during all periods. At 40 days, the ANB was higher in the

PPS group than in the P group (P , .001); the CFT was statistically higher in the CPS group than the PPS group

(P , .001) and was higher in the CPS group than the C group (P , .001). At 40 and 90 days, the CIC was higher in

the P group than in the C group (P , .001). In conclusion, the copolymer had biocompatibility, enhanced bone

healing, and presented osteoconductive properties, thus raising the contact between bone and implant, even

without primary stability.

Key Words: dental implants, bone substitutes, osseointegration, bone regeneration.

INTRODUCTION

The use of dental implants represents an

important treatment for edentulous pa-

tients (partial or total); however, success

depends on intimate contact of bone

tissue with the implant, that is, bone

integration. The implant remains in the receptor

because of the presence of primary stability, and

this has been identified as a prerequisite for

1 Department of Morphology, Piracicaba Dental School –UNICAMP, Piracicaba, Sao Paulo, Brazil.2 Department of Surgery and Integrated Clinic, Faculty ofDentistry of Aracatuba – UNESP, Aracatuba, Sao Paulo, Brazil.3 University Center of Araraquara – UNIARA, Araraquara, SaoPaulo, Brazil.4 Department of Oral and Maxillofacial Surgery and Traumatol-ogy, Faculty of Dentistry of Araraquara – UNESP, Araraquara, SaoPaulo, Brazil.5 Department of Basic Sciences, Faculty of Dentistry of Aracatu-ba, Sao Paulo, Brazil.* Corresponding author, e-mail: [email protected]: 10.1563/AAID-JOI-D-10-00102

Journal of Oral Implantology 449

RESEARCH

obtaining osseointegration.1 Bone density, propor-tion of cortical and medullar bone, quality of bonetissue, presence of dental alveoli after toothextraction, and inadequate preparation of thereceptor are factors that may interfere in theprimary implant stability.2

Bone tissue has a high capacity for repair andregeneration, and its original structure and functionmay be completely restored. However, in somesituations, because of the size of the bone defect, thebone tissue does not regenerate completely. In anattempt to promote primary implant stability,especially in cases of poor-quality bone, cliniciansuse bone grafts as well as allogeneic,3 xenogenous,4–

6 and, more recently, synthetic bone substitutes.7

To avoid or minimize the limitations of autoge-nous bone grafts, especially considering their limitedavailability for large reconstructions and surgicalmorbidity, researchers have had good results usingbiomaterials8 or bone substitutes.9 Other research-ers have reported that polymeric materials have theadvantages of biocompatibility, good mechanicalproperties, easy handling,10,11 and inhibition of theinfectious and immunologic complications reportedwith materials of biological origin.12,13 Moreover,these materials are bioabsorbable through meta-bolic hydrolysis, so patients do not have to undergosurgery to remove the device.14

The main polymeric materials currently studiedare polylactic acid (PLA) and polyglycolic acid (PGA),alone or as copolymers.15 Rabbit studies haveshown that PGA is degraded more quickly (2months) than PLA (12 months).16 It is also knownthat the hydrolysis of copolymers of PLA/PGA insolid form results in the release of lactic acidmonomers, which are oxidized to form pyruvicacid.17 Rimondini et al18 analyzed bone repair afterimplantation of a copolymer of PLA/PGA (50:50proportion) used as bone substitute and concludedthat this copolymer, dispersed in a hydrosolublematrix, is osteoconductive in critical bone defects.Several studies have shown beneficial effects ofthese copolymers in animals and humans,19–21

focusing on their osseoconductive properties be-cause they work as a frame for the replacement ofthe extracellular matrix.18,22–24

Given the importance of primary implant stabil-ity in biomechanics and subsequent osseointegra-tion, and considering the natural or inducedanatomic changes in bone tissue, the combination

of resorbable biomaterials at the site of implantinstallation becomes important. Among them is thecopolymer of PLA/PGA, which could contribute tothe temporary stability of implants by modifyingthe biomechanics of the bone-implant interface andcould promote bone conduction.

The purpose of this study was to evaluate theassociation of the PLA/PGA copolymer arounddental implants installed with or without primarystability through the histometric analysis of thebone-implant interface.

MATERIALS AND METHODS

We used 10 white male rabbits (New Zealand,albinus variation) aged 5 months and weighing 3 to4 kg The animals were kept in individual cages andfed a standard diet of solid feed (Procoelho, Primor,Sao Paulo, Brazil) and water ad libitum. The study,submitted to the Ethics Committee on AnimalExperiments of the Faculty of Dentistry of Aracatu-ba-UNESP, was approved under protocol number2007/07948–9.

Experimental Surgery

Food was withheld from the rabbits for 8 hoursbefore the surgery, and rabbits were sedated by acombination of 50 mg of intramuscular ketamine(Vetaset, Fort Dodge Animal Health Ltd, Campinas,Sao Paulo, Brazil) and 5 mg/kg xylazine hydrochlo-ride (Dopaser, Laboratory Calier of Brazil Ltd,Osasco, Sao Paulo, Brazil) and received mepivacainehydrochloride (0.3 mL/kg, Scandicaıne 2% withepinephrine 1:100 000, Septodont, Saint-Maur-des-Fosses, France) as local anesthesia and hemostasisof the operative field.

After the rabbits were sedated, trichotomy wasperformed in the medial portion of the right tibia.Polyvinylpyrrolidone-iodine detergent (10% PVP-I,Riodeine detergent, Rioquımica, Sao Jose do RioPreto, Brazil), associated with topical PVP-I, wasapplied as an antiseptic to the region to be incised.

Using a #15 blade (Feather Industries Ltd, Tokyo,Japan) an incision about 3 cm long was made in thetibial metaphysic region (left and right). The bonetissue was then exposed using periosteal retractorsto receive implants.

Next, we installed 40 titanium implants that hadbeen surface treated by acid etching and sand-blasting (SLA, Connection, Sao Paulo, Brazil). These

450 Vol. XXXVIII / Special Issue No. One / 2012

Analysis of Bone Repair Using a PLA/PGA Copolymer

implants, which have a square implant collar, were2.6 mm in diameter and 6.0 mm in height and weresterilized by gamma rays.

Each rabbit received 4 implants, 2 in each tibialmetaphysis; a distance of approximately 10 mm waskept between them. In the right tibia, the implantswere installed with primary stability, and in the lefttibia, they were installed without stability, creating 4experimental groups:

Control with primary stability (CPS): The implantswere installed in the bone defect after osteotomy of2.0 mm in diameter and 6.0 mm deep, were filledonly with blood clot, and had primary stability.

Control without primary stability (C): The implantswere installed in the bone defect after osteotomyof 3.0 mm in diameter and 6.0 mm deep, werefilled only with blood clot, and had primarystability.

Polymer with primary stability (PPS): The implantswere installed after osteotomy of 2.0 mm indiameter and 6.0 mm deep, were associated withthe copolymer of PLA (70%) and PGA (30%) in a1:1 proportion (VETEC Fine Chemicals Ltd, Duquede Caxias, RJ, Brazil), were heated between 100and 1508C to gel consistency, and had primarystability.

Polymer without primary stability (P): The implantswere installed after osteotomy of 3.0 mm indiameter and 6.0 mm in depth, were associatedwith the copolymer of PLA (70%) and PGA (30%) ina 1:1 proportion (VETEC Fine Chemicals Ltd), wereheated between 100 and 1508C to gel consistency,and did not have primary stability.

The copolymer was prepared by mixing PLA(70%) and PGA (30%) (in the proportion of 1:1) andthen adding this mixture to the polyvinyl alcohol,heating the mixture to a temperature between 100and 1508C, until the liquid reached the consistencyof a gel after polymerization.

We used an electric motor with a final speed of1600 rpm to prepare bone defects at a 16:1reduction contra-angle (Kavo, Santa Catarina, Brazil).Preparation of receptors began with a cutter todelimit the location of the implants and break thecortical bone. Then we used the helical cutter at 2.0mm for the groups in which the implants wereinstalled with primary stability (CPS and PPS). Ingroups C and P, we used the same sequence of

cutters outlined earlier, adding a pilot of 2.0 mm/3.0mm and, finally, the helical cutter 3.0 mm (Connec-tion, Sao Paulo, Brazil) was used sequentially alongwith irrigation with a solution of sodium chloride0.9% (Darrow, Rio de Janeiro, Brazil) during thepreparation. In the PPS and P groups, the implantswere surrounded by the copolymer; the copolymerwas also placed on the surgical defect before theimplant was installed. The defects involved only thesuperior cortical bone (monocortical bone).

Tissues were sutured in planes using absorbablethread (Poligalactina 910 - Vycril 4.0, Ethicon,Johnson Products, Sao Jose dos Campos, Brazil)with continuous stitches in the deep plane andmonofilament (Nylon 5.0, Ethicon, Johnson) withinterrupted stitches in the more external plane.

In the immediate postoperative period, therabbits received intramuscular pentabiotic (0.1 mL/kg, Fort Dodge Animal Health Ltd), repeated after 5days. They also received dipirone (1 mg/kg, AristonChemical and Pharmaceutical Industries Ltd, SaoPaulo, Brazil) totaling 3 doses. Euthanasia wasperformed at 40 and 90 days after surgery, 5 rabbitsper period, by anesthetic overdose.

There were no complications in the transsurgicaland postoperative periods. The animals showed nosigns of infection at the incision site.

Histologic and Histometric Analysis

After euthanasia, the right and left tibial metaphy-ses were removed and margins were reduced about1 cm to the fullest extent of the defects. They werefixed in buffered formalin 10% (Analytical Reagents,Dynamics Odonto-Hospitalar Ltda, Guarulhos, SP,Brazil) for 48 hours and washed in water for 24hours. After fixation, the pieces went through thedehydration stage via a gradually increasing se-quence of alcohols—70, 90, 95, and 100; thesolution was changed every 3 days. Dehydratedparts were placed in an orbital shaker (Kline CT -150, Cientec - Laboratory Equipment, Piracicaba, SP,Brazil) every day for 4 hours.

After dehydration, the pieces were immersed inacetone (Labsynth Products Laboratories Ltda,Diadema, SP, Brazil) for 24 hours and then placedin a solution of acetone and slow polymethylme-thacrylate (PMMAL; Classico, Articles Dental Classic,Sao Paulo , SP, Brazil) at a ratio of 1:1. Subsequently,the pieces were immersed in 3 baths of PMMAL,and the catalyst benzoyl peroxide (1% Riedel - De


Freire et al

Haen AG, Seelze-Hannover, Germany) was added tothe last bath.

The last bath (PMMAL and catalyst) was per-formed with the pieces placed in glass jars with lidsand kept at room temperature for about 1 week sothat the resin cured. After polymerization, theblocks with the pieces were initially bisected atthe mesiodistal place using a floppy-sided diamonddisc (KG Sorensen, number 7020, Sao Paulo, Brazil).Manual progressive wear was applied with wetsandpaper granulation 3M 220, 400, 600, and 800(3M Brazil, Sorocaba, SP, Brazil) under fluorescentlight, gradually up to a thickness of 100 mm indiameter in the longitudinal implants.

The histologic sections were fixed on glass slidesusing epoxy adhesive (Araldite Epoxy Systems forLamination, Huntsman, MAXEPOX, Santo Amaro, SaoPaulo, Brazil) and stained with alizarin red andStevenel blue. Coverslips were mounted with Per-mount (Fisher Chemical, Fisher Scientific, Waltham,Mass). After fixing the coverslips, the edges wereinsulated with enamel to prevent the depletion of oil,thereby preventing the piece from drying out.

The images were captured using a conventionaloptical microscope (Leica Microsystems AristoplanLeitz, Benshein, Germany) coupled with a digitalcamera for image capture (Leica DFC 300FX, LeicaMicrosystems, Heerbrugg, Switzerland) and con-nected to a computer with a software analyzer forscanned images (Leica Camera Software Box, LeicaImaging Manager-IM50 Software).

For the histometric analysis, we used theImageLab 2000 program, version 2.4 (DiracomBioInformatica, Vargem Grande do Sul, Sao Paulo,Brazil), and calculated the linear extent of contactbetween the newly formed bone (ANB) tissue(stained with alizarin red) and the implant surfaceon the implant collar and the on the first thread andin the area of ANB on the first thread on each side ofthe implant (located in the cortical bone) because ofthe anatomy of the receptor (wide medullar space),similar to the method of Johansson et al.25

The data were converted to percentages andcompared using analysis of variance (ANOVA) andTukey test for multiple comparisons betweengroups and time periods, adopting a significancelevel of 5%. Mean values of ANB, contact betweenthe bone and implant surface on the implant collar(CIC), and contact between the bone and implantsurface on the first thread (CFT) were analyzed.

RESULTS

Clinical Analysis

After reopening the tibia to removing the pieces,the implants were observed to be stable at 40 and90 days, with the newly formed bone covering theimplant collar (Figure 1). Implants in the primarystability groups presented in a three-dimensionalposition closer to the installation position, and thegroups without stability presented in a proneposition compared with the initial installation. Inthe groups without primary stability, the placementof implants from P group was less inclined than theplacement of implants from the C group (Figure 1).

In groups where the implants were installed withprimary stability, there was no clinical change in theposition of the implants after osseointegration. Inthe groups where the implants were installedwithout any primary stability, during the reopeningand exposure of the implants, it was found thatthey were a little inclined (or angulated) becausethey were not stability. This small tilt (or angulation),observed clinically in groups of implants placedwithout primary stability, was lower when theseimplants were associated with the copolymer ofPLA/PGA. The copolymer fills up the spacesbetween the implant and the surgical site, whichhelps maintain the primary position of implantsinstalled without stability by producing a gelconsistency.

Histologic and Histometric Analysis

The qualitative results show that there was newbone formation in all groups and during all periods.In groups with stable implants (CPS and PPS),mature newly formed bone tissue (stained withalizarin red) was observed, predominantly in contactwith the implant collar, at both time periods(Figures 2a through 5).

The presence of mature bone tissue throughoutmost of this area was observed because the implantcollar was located in the cortical bone, where therewas higher bone formation (Figures 2a and 3a). Atthe implant threads, the bone formation was lowerbecause these areas are located wholly or partiallywithin the medullary canal, where bone formation isreduced. Adjacent to the newly formed bone, weobserved the presence of fibrous connective tissue(stained Stevenel blue) in both groups and periods(Figures 2b, 3b, and 4).



In the group with the PLA/PGA copolymer (PPS

group), at 40 days the presence of the copolymer

was observed mainly on the threads, that is, near the

marrow canal. At this area, connective tissue and a

high presence of cells and numerous osteoblasts

were observed around the remainder of the

polymer, which was being degraded and replaced

by the adjacent collagenous matrix (Figure 4b). At 90

days there was less copolymer in the area of the

threads of the implant (medullary area) (Figure 5b).

In groups where the implant was not stable (C and P

groups), we observed the presence of mature bone

tissue in contact with the implant collar (cortical

bone) in the 2 studied periods (40 and 90 days).

For comparison between groups and periods,

ANOVA was applied for the 3 criteria for analysis

(ANB, CFT, and CIC), and there was a statistically

significant difference between groups for each

criterion (P , .001). Therefore, the Tukey test was

applied for multiple comparisons between groups

and periods to verify in which groups these

differences were present (P ¼ .05).

Comparisons between the groups with primary

stability (CPS and PPS groups) and without primary

stability (C and P groups) showed that, after 40 days,

the ANB was higher in the PPS group than in the P

group (P , .001), and CFT was higher in the CPS

group than in the C and PPS groups (P ,.001), that

is, the lack of primary stability and the presence of

the copolymer delayed the bone-formation process.

In CIC there was a statistically significant

difference in the P group compared with the C

group at 40 days (P¼ .03) and 90 days (P , .001).

Tables 1, 2, and 3 show the mean, SD, and

maximum and minimum values for the different

FIGURES 1 AND 2. FIGURE 1. Clinical analysis of the left tibia at (a) 40 and (b) 90 postoperative days. The arrow indicates that thepolymer without primary stability group implant has a smaller inclination than the control without primary stability groupimplant. At 90 days the implant was under bone tissue. FIGURE 2. The bone tissue filled the areas of the implant collar in (a)the control with primary stability group and (b) at the coronal first thread in the polymer with primary stability (PPS) groupat postoperative day 40. On the implant collar in the PPS there was contact with fibrous tissue.


Freire et al

FIGURES 3–5. FIGURE 3. (a) At 90 days, the bone tissue also filled the areas of the implant collar in the control with primarystability. (b) Bone tissue filled the areas on the first coronal thread in the polymer with primary stability (PPS) group. On theimplant collar in the PPS group there was contact with fibrous tissue. FIGURE 4. (a) The control without primary stability (C)group showed the bone tissue located at the areas of the implant collar. (b) In the polymer without primary stability (P)group, there was contact between bone and the threads in the medullar area at 40 days. Note the presence of the polylacticacid/polygalactic acid copolymer located in the medullar space. FIGURE 5. At 90 days, in (a) there was discontinuancebetween the bone tissue and the implant surface on the implant collar (C group). (b) In the P group, the bone filled theimplant collar and the first coronal thread areas, and there was major contact between the implant surfaces.



groups and time periods, according to the criteriaevaluated (ANB, CFT, and CIC).

DISCUSSION

The use of rabbit tibia bone as a model to evaluatethe osseointegration of different types of implantshas been widely used in the literature. The mostused place in this experimental model is the medial-proximal region of the tibia26 and the tibialmetaphysis.27

The primary stability of implants is one of the mainfactors influencing the survival rates of the implant. Itis considered a prerequisite for establishing mechan-ical support, which is essential to the process ofosseointegration,2 as unstable implants result infibrous encapsulation.28 In this study the presenceof new bone formation was verified around implantsinstalled with and without primary stability andconfirmed by qualitative and quantitative analysis.However, in the groups with implants installedwithout primary stability, the bone formation waslower than in the stable groups after 40 days. The

movement of the implant during the bone-healingprocess leads to a lack of mechanical support and

initial delay and consequent reduction in bone

formation and establishment of an interface with

the implant surface. At 90 days, this difference is notobserved because of the secondary stabilization of

the implant. Akimoto et al29 concluded that the width

of the bone defect directly influences the percentage

of bone-implant contact; however, in their study theimplants were installed with primary stability.

Although high success rates have been reported

with the use of osseointegrated implants,30 failuresmay be observed in bone of poor quality or in

situations of reduced bone volume.31 Moreover,

after tooth extraction, the alveolus often presents

dimensions larger than the diameter of a conven-tional implant, forming a gap that affects the

acceptable bone-implant contact. Use of the PLA/

PGA copolymer favored the primary placement of

implants and subsequent bone formation at 40 and90 days in groups without primary stability. This

finding may be explained by the statistical difference

between groups P and C in both periods. In the

TABLE 1.

Maximum, mean, minimum, and SD of ANB (%)*

ANB CPS Group C Group PPS Group P Group

40 days Maximum 72.89 77.94 90.33 68.44Mean 68.50 72.81 80.06 62.96

Minimum 64.34 68.36 64.66 57.50

SD 3.23 3.74 10.69 4.1490 days Maximum 95.78 86.58 94.76 81.76

Mean 91.42 82.73 88.11 79.77Minimum 84.39 78.25 80.43 74.17

SD 4.30 3.50 5.98 3.24

*ANB indicates area of newly formed bone; CPS, control with primary stability; C, control without primary stability; PPS,polymer with primary stability; P, polymer without primary stability.

TABLE 2.

Maximum, mean, minimum, and SD of CFT (%)*

CFT CPS Group C Group PPS Group P Group


Minimum 75.82 58.17 61.67 52.03

SD 3.62 1.82 2.13 1.9990 days Maximum 88.57 87.89 81.08 67.98

Mean 80.20 84.42 76.44 66.53Minimum 66.03 79.56 71.28 63.54

SD 10.09 3.43 3.50 1.77

*CFT indicates contact between the bone and implant surface on the first thread; CPS, control with primary stability; C,control without primary stability; PPS, polymer with primary stability; P, polymer without primary stability.


Freire et al

analysis of the CIC of these groups, the presence ofthe copolymer favored the maintenance of primaryplacement of implants, serving as a mechanicalsupport and a framework for the process of boneformation18 and reducing movement.

In groups of implants with primary stability, ahigher bone formation was observed in the CPSgroup than in the PPS group after 40 days. Thisresult is related to the presence of the copolymer,which undergoes a process of degradation byhydrolysis as it is gradually replaced by newlyformed bone tissue, delaying the repair process.However, the polymer was demonstrated to beosteoconductive because of the presence of a largepercentage of new bone formation in the PPS and Pgroups at 90 days (mean 88.11% and 70.77%,respectively), as noted by other authors.18,22–24

The association of the PLA/PGA with otherbiomaterials is also being tested, as reported byHassan.32 This author evaluated the association of thispolymer with autogenous bone graft, and the resultsshowed significant reduction of probing pocketdepth and gains in attachment level in patients withdehiscence around immediate dental implants, sug-gesting that this as an excellent biomaterial polymericbone substitute. Thus, maintenance of the primaryposition of the implants, as shown in our study and inthe study by Hassan32 may be essential for the successof techniques that involve immediate dental implants.

Therefore, considering the bone formationobserved mainly at 90 days in all groups andperiods in this study, and based on the methodol-ogy and results, we concluded that the PLA/PGAcopolymer showed biocompatibility and allowednew bone formation in contact with the implant.The presence of the copolymer delayed boneformation in the group without primary stability

but helped to maintain the primary position in thegroups without stability. Moreover, osseointegra-tion occurred in both groups, even in the absenceof primary stability of implants.

We suggest the need for new research consid-ering this proposed experimental methodology forevaluating different methods of analysis (such as

biomechanics, immunohistochemistry, and thescanning electron microscopy) and different periodsand types of implants, with or without applicationof immediate or late prosthetic loads.

The presence of the copolymer resulted in lessbone formation in the group without stability butresulted in more bone formation in the group with

stability. On the other hand, the copolymerpromoted major linear contact between bone andimplant, especially in the group without primarystability, at the implant collar, where it wassurrounded by cortical bone.

Thus, the PLA/PGA copolymer has an osteocon-ductive property and enhances bone healing insituations that involve a lack of bone tissue and in

critical bone defects. Moreover, this study contrib-uted additional information about the use of thePLA/PGA copolymer as a bone substitute.

ACKNOWLEDGMENT

The authors are grateful to the FAPESP (Fundacaode Amparo a Pesquisa do Estado de Sao Paulo - SaoPaulo Research Foundation) for financial support.

ABBREVIATIONS

ANB: area of newly formed bone tissue

C: control without primary stability

TABLE 3.

Maximum, mean, minimum, and SD of CIC (%)

CIC CPS Group C Group PPS Group P Group


Minimum 47.78 45.69 48.88 57.61

SD 4.02 1.68 4.42 2.1090 days Maximum 77.91 67.83 80.01 88.62

Mean 72.95 64.58 76.99 77.91Minimum 65.82 59.97 74.07 68.43

SD 4.87 2.96 2.21 7.61

*CIC indicates contact between the bone and implant surface on the implant collar; CPS, control with primary stability; C,control without primary stability; PPS, polymer with primary stability; P, polymer without primary stability.



CFT: contact between the bone and implant surfaceon the first threadCIC: contact between the bone and implant surfaceon the implant collarCPS: control with primary stabilityP: polymer without primary stabilityPGA: polyglycolic acidPLA: polylactic acidPMMA: polymethylmethacrylatePPS: polymer with primary stability

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