Membranes for guided tissue and bone · PDF file · 2014-03-02Membranes for guided...

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For citation purposes: Zhang Y, Zhang X, Shi B, Miron RJ. Membranes for guided tissue and bone regeneration. Annals of Oral & Maxillofacial Surgery 2013 Feb 01;1(1):10.

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Membranes for guided tissue and bone regenerationY Zhang*, X Zhang, B Shi, RJ Miron

AbstractIntroductionSince the clinical use of dental membranes in the mid-1980s, guid-ed bone regeneration procedures have become the standard in den-tal surgeries requiring space provi-sion. A number of advancements have been made over the past 20 years in terms of their fabrication development. This review paper dis-cusses original polytetrafluoroethyl-ene non-resorbable membranes and the more recently employed innova-tive techniques to alter resorption periods in resorbable membranes. Furthermore, insight into future de-velopments in membrane fabrication as well as platelet-rich fibrin mem-branes are discussed that will direct the next generation of guided bone regeneration.ConclusionThere have been major advance-ments since the original expanded polytetrafluoroethylene membranes. Surgical procedures are no longer necessary as they cause discom-fort to patients. Synthesis and natu-ral biomaterials have been used in dentistry successfully for over 20 years, and their mechanical proper-ties and degradation rates are being improved constantly. Furthermore, osteoconductive calcium phosphates and bioactive growth factors are now being incorporated to allow better bone formation.

IntroductionPrinciple of guided tissue and bone regeneration—its originIt was not always believed that the periodontal ligament cells were re-sponsible for the healing capabili-ties in the periodontium1. From the 1970s until the mid-1980s, it was widely accepted and believed that the cells capable of regeneration of the periodontium were found in the alveolar bone2. It was not until the late 1980s and conclusively at the be-ginning of the 1990s following a se-ries of experiments in monkeys that conclusive evidence supported that progenitor cells in the periodontium were from the periodontal ligament tissue3–5.

Based on these results, it was hy-pothesized that in order to optimize regeneration, if cells derived from the periodontal ligament and alveo-lar bone were exclusively allowed to repopulate the root surface away from the faster growing epithelium and gingival connective tissues, a higher regenerative potential would be observed; thus, the development of a “membrane-like” mechanical barrier was introduced6. The devel-opment of “guided tissue regenera-tion” (GTR) was created in order to selectively guide tissue regeneration in the periodontium following peri-odontal disease. Following flap sur-gery in monkeys exposed to plaque for 6 months, a cellulose acetate laboratory filter or expanded pol-ytetrafluoroethylene [ePTFE]) was used to successfully prevent gingi-val connective tissue from contact-ing the root surface during healing and to produce a space for tissue ingrowth of the periodontal liga-ment6. Following 3 months of heal-ing, it was concluded by histological evaluation that the test membranes

protested from epithelial down growth exhibited considerably more new attachment and bone re-growth6. The results from this study confirmed the hypothesis that by selectively controlling the prolif-eration of the periodontal ligament cells and preventing contact from epithelium and connective tissues, the space-maintaining capability al-lowed for increased r egeneration of the attachment apparatus of the tooth. Subsequently, Buser et al. introduced the basic principles of “guided bone regeneration” (GBR), that is providing the cells from bone tissues with a space intended for bone regeneration away from the surrounding connective tissue, by inserting barrier membranes to a bone defect7. The work from the above-mentioned authors has been confirmed and reproduced in a num-ber of animal and clinical studies in-creasing various periodontal defects including intrabony, furcation reces-sion and supra-alveolar defects8–11. Various approaches to increase new tissue and promote bone regenera-tion have been developed and compared (Table 1). The principles

Membranes for guided tissue and bone regenerationThe very first application of a mem-brane providing evidence that GTR could enhance regeneration of the human periodontium was a cellu-lose acetate laboratory filter by Mil-lipore12. Since then, a wide range of new membranes has been designed for various clinical scenarios, each

* Corresponding authorEmail: [email protected]

The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, People’s Republic of China.

and limitations of each method sug-gest that GBR procedures are a bett-er solution to non-membrane supp-orted healing. This paper discusses the membranes used for guided tiss-ue and bone regeneration.

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when compared to resorbable mem-branes. They have a more predictable profile during the healing process for their adequate mechanical strength, and they are easy to handle in clinics16.

PTFE membranePTFE membranes were first intro-duced to dentistry in 1984; however, the membranes had been used clini-cally for some previous years as a vascular graft material for hernia repair17,18. Both sides of the porous structure of e-PTFE have their own features19: on one side, an open mi-crostructure collar of 1 mm thick and 90% porosity retards the growth of the epithelium during the early wound healing phase; on the other side, a 0.15 mm thick and 30% po-rous membrane provides space for new bone growth and acts to prevent fibrous ingrowth. The average heal-ing period after in vivo implantation is approximately 3–6 months (Table 2).

The advantages of d-PTFE, which feature 0.2 µm submicron pores on their membranes, is that they do not require primary closure and preserve the full width of keratinized mu-cosa20. Compared with the conven-tional e-PTFE, d-PTFE demonstrates

Non-resorbable membranesNon-resorbable membranes include expanded, high-density and Titanium-reinforced ePTFE (e-, d-PTFE and Ti-e-PTFE) and titanium mesh (Ti-mesh)13. Although a number of animal studies involving a variety of defect configu-rations and human histological data after treatment of intrabony lesions with ePTFE membranes demonstrate higher levels with clinical attachment level (CAL) gain and residual probing depth14, the requirement of a second surgical intervention to remove the barrier 4 to 6 weeks after implanta-tion is a significant drawback15. The need for a second surgery may injure and/or compromise the obtained re-generated tissue, since it is known that flap elevation results in a certain amount of crestal resorption of the al-veolar bone15. Furthermore, the use of non-resorbable membranes involves extra surgical times, which leads to increased costs and patient dis-comfort. These undesirable char-acteristics are often weighed with the positive effects of using non- resorbable membrane which in-clude effective biocompatibility and ability to maintain sufficient space in the membrane for longer periods

possessing distinct advantages and disadvantages. As a medical application in dental implantol-ogy, barrier membranes should fulfil some fundamental requirements: • Biocompatibility—the interaction

between membranes and host tissue should not induce adverse effect;

• Space-making—the ability tomaintain a space for cells from surrounding bone tissue to mi-grate for stable time duration;

• Cell-occlusiveness—prevention offibrous tissue that delay bone for-mation from invading the defect site;

• Mechanical strength—proper physical properties to allow and protect the healing process, in-cluding protection of the underly-ing blood clot;

• Degradability—adequate degra-dation time matching the regener-ation rate of bone tissue to avoid a secondary surgical procedure to remove the membrane.

Several commercially available membranes, according to non- resorbable, synthetic resorbable and natural biodegradable materials, are classified in Table 2.

Table 1 Different approaches to encourage bone regenerationApproaches Principles Typical examples LimitationsOsteoconduction The process in which the bone

graft material acts as a scaffold for new bone formation on the native bone

Autogenous bone graft Bone augmentation cannot achieve long-term stability and predictability without using barrier membrane

Distraction osteogenesis

Describes the spontaneous bone regeneration within an area created by gradual separation of two bone ends in a man-made fracture

Repair fracture in the jaw Outcomes may be unpredictable and the man-made fracture would be risky

Osteoinduction Recruit ideal factors such as mesenchymal stem cells, osteoprogenitor cells and growth factors to stimulate new bone growth

Bone morphogenetic proteins (BMPs)Bone marrow mesenchymal stem cells (BMMSCs)

Easy access to translating basic scientific research on induction of bone into reliable clinical applications

GBR By barrier membranes to maintain sufficient space for the newly formed bone to fill in

Non-resorbable and resorbable membranes applied to implant surgery

Mechanical and chemical properties of membranes affects the final results

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Table 2 Classification of different membranes in GBR

Membranes Commercial name

Manufacturer and nation Material Properties Comments Reference

Non-resorbable membranes

e-PTFE

Gore-TexW. L. Gore & Associates, Inc., USA

e-PTFEGood space maintainer

Easy to handle

Longest clinical experience

23,24

Gore-Tex-TIW. L. Gore & Associates, Inc., USA

Ti-e-PTFE

Most stable space maintainer

Filler material unnecessary

Titanium should not be exposedCommonly used

in ridge augmentation

25

d-PTFE

High-density Gore-Tex

W. L. Gore & Associates, Inc., USA

d-PTFE

0.2 μm pores Avoid a second-ary surgery

26

CytoplastOsteogenics Biomedical.,

USA<0.3 μm pores Primary closure

unnecessary27

TefGen FDLifecore Bio-medical, Inc.,

USA0.2–0.3 μm pores Easy to detach 28

Non-resorba-ble ACE

Surgical supply, Inc., USA

<0.2 μm pores0.2 mm thick

Limited cell proliferation

29

Tita-nium mesh

Ti-Micromesh ACE

Surgical supply, Inc., USA

Ti

1,700 mm pores0.1 mm thick

Ideal long term survival rate

30

Tocksystem Mesh

Tocksystem, Italy

0.1–6.5 mm pore0.1 mm thick

Minimal resorption and inflammation

31

Frios BoneShields

Dentsply Fria-dent, Germany

0.03 mm pores0.1 mm thick

Sufficient bone to regenerate

31

M-TAM 1,700 mm pores0.1–0.3 mm thick

Excellent tissue compatibility

32

Synthetic resorbable membranes

OsseoQuestW. L. Gore & Associates, Inc., USA

Hydrolyzable polyester

Resorption: 16–24 weeks

Good tissue integration

33

Biofix Bioscience Oy, USA

Polyglycolic acid


Isolate the space from cells from soft tissue and

bacteria

34

Vicryl Johnson & Johnson, USA

Polyglactin 910

Polyglicolid/polyl actid

9:1

Well adaptableResorption: 4–12

weeks

Woven membrane

Four prefabri-cated shapes

35

Atrisorb Tolmar, Inc., USA

Poly-DL-lactide and

solvent


Interesting resorp-tive characteristics

Custom fabricated membrane

“ Barrier Kit”

36

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Table 2 (continued)

EpiGuideKensey Nash corporation,

USA

Poly-DL-lactic acid

Three-layer mem-brane


Self-supportingSupport devel-oped blood clot

37

ResolutW. L. Gore & Associates, Inc., USA

Poly-DL-lactid/

Co-glycolid

Resorption: 10 weeks

Good space maintainer

Good tissue integration

Separate suture material

38

Vivosorb Polyganics B.V. NL

DL-lactide-ε-caprolactone

(PLCL)

Anti-adhesive barrier

Up to 8 weeks’ mechanical prop-

erties

Act as a nerve guide

39

Natural biodegradable material

Plasma rich in growth

factors(PRGF-Endoret)

BTI Biotechnology

Institute, Vitoria, Spain

Patients’ own blood

Abundant growth factors and pro-

teins mediate cell behaviors

Different formula-tions for various

usagesTotal resorption

Enhance osse-ointegration and

initial implant stability

Promote new bone formationEncourage soft tissue recovery

40

Bio-Gide Osteohealth Company, SUI

Porcine I and III

Resorption: 24 weeks

Mechanical strength: 7.5 MPa

Usually used in combina-

tion with filler materials

41

Bio-mend Zimmer, USA Bovine I

Resorption: 8 weeks

Mechanical strength: 3.5–22.5

MPa

Fibrous networkModulate cell

activities42

Biosorb membrane 3M ESPE, USA Bovine I Resorption: 26–38

weeksTissue

integration43

Neomem Citagenix, CAN Bovine I

Double-layer product


Used in severe cases

44

OsseoGuard BIOMET 3i, USA Bovine I Resorption: 24–32

weeks

Improve the aesthetics of the final prosthetics

45

Ossix OraPharma, Inc., USA Porcine I Resorption: 16–24

weeksIncrease the woven bone

46

obvious advantages as they prevent infections and easy operation for re-moval (Table 2).

Titanium meshTitanium-reinforced barrier mem-branes were introduced as an option for GBR, because they provide

advanced mechanical support which allows a larger space for bone and tissue regrowth. The exceptional properties of rigidity, elasticity, sta-bility and plasticity make Ti-mesh an ideal alternative for e-PTFE products as non-resorbable membranes21. Ra-khmatia et al. demonstrated that

there are four main advantages of Ti-mesh membranes over their al-ternative PTFE membranes: (1) rigidity provides extensive space maintenance and prevents contour collapse; (2) elasticity prevents mucosal compression; (3) its stabil-ity prevents graft displacement and

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(4) plasticity permits bending, con-touring and adaptation to any unique bony defect. The main disadvantage of Ti-mesh membranes is increased exposure due to their stiffness and also a more complex secondary sur-gery to remove them.

Resorbable membranesThe advantage of resorbable mem-branes is that they permit a single-step procedure, thus alleviating patient discomfort and costs from a second procedure, avoiding the risk of additional morbidity and tissue damage. The main disadvantage of resorbable membranes is the unpre-dictable resorption time and the de-gree of degradation, which directly affects bone formation22. The ideal membrane should be capable of be-ing degraded or resorbed over time at the same rate that bone formation occurs. A list of studies describing re-sorption rates is given in Table 223–46.

Synthetic resorbable membranesThis series of resorbable mem-branes mainly consist of poly-esters [e.g., poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly (ε-caprolactone) (PCL)] and their co-polymers47. Collagen and aliphat-ic polyesters, such as polyglycolide or polylactide, are derived from a variety of origins and are fabricated with different approaches to become membranes for GBR (Table 2). Poly-glycolide or polylactide can be made in large quantities, and the wide range of available materials allows for the creation of a wide spectrum of membranes with different physi-cal, chemical and mechanical prop-erties. Interestingly, the resorption of various membranes occurs via different pathways. In a review pa-per on this subject48, Tatakis et al. describe that a large majority of collagen membranes is resorbed by enzymatic activity of infiltrating macrophages and polymorphonu-clear leucocytes, while polymers are typically degraded through

hydrolysis and the degradation products are metabolized through the citric acid cycle.

Membranes based on natural materialsThe highest number of reported clinical studies involves the use of biodegrad-able resorbable membranes from nat-ural materials (Table 2). Membranes based on natural materials are typi-cally derived from human skin, bovine achilles tendon or porcine skin, and can be characterized by their excellent cell affinity and biocompatibility. The main drawbacks of these membranes are the potential of losing space main-tenance ability in physiological condi-tion, high cost and possible danger of transmitting disease to humans when applying animal-derived collagen49. Figure 1 demonstrates a scanning electron micrograph of a highly uti-lized natural membrane from bovine origin commonly used in GTR and GBR procedures (BioGuide, Geistlich Pharmaceuticals, Switzerland).

Focus on plasma-rich proteins (PRPs) as growth factors and membranesPRPs isolated from platelets are a source of autologous growth factors that have been used for a variety of medical applications50,51. The de-velopment of platelet concentrates was first described as early as 1970 as a fibrin glue and has since ex-ploded in popularity. Since 1990, the development of basic concepts

in the wound-healing process has recognized several key components in blood that act to accelerate the healing of wounded tissues. Platelet-rich plasma was one of the first au-tologous modifications to fibrin glue that has been used with apparent clinical success in dentistry. This first generation of platelet concentrates contained approximately 95% plate-lets isolated through centrifugation. Although many growth factors are isolated via this method, the use of additional anticoagulants limits the natural healing process (Table 3)50,51.

More recently, a natural autologous membrane has been developed through platelet concentrations—that of platelet-rich fibrin (PRF)52–54. The advantages of this membrane are that they are entirely autolo-gous and do not contain any anticoagulants or bovine thrombin such as PRP. The PRF preparation protocol is very simple and inexpensive and is a great alternative to non-resorbable and resorbable membranes. Around 5 ml of whole venous blood is collected in sterile tubes and spun at 3,000 revo-lutions per minute for 10 min in a cen-trifuge tube55. The blood is then settled into three layers: a red lower layer containing red blood cells, an upper clear coloured cellular plasma layer and the middle fraction containing the fibrin clot (Figure 2A). The middle lay-er can then be collected and shaped as desired and used as a PRF membrane (Figure 2B). This fibrin matrix can then be either used as a membrane

Figure 1: Scanning electron microscopy of a porcine collagen membrane at magnifications of (a) 100× and (b) 400×, respectively.

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Current trends in the development of membranesMany advancements and modifica-tions have been made to membranes in order to improve the mechanical properties, degradation periods via cross-linking techniques and also bio-compatibility. Herein, we look at the

Declaration of Helsinki (1964), and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies.

alone or combined with other bone grafts facilitating bone regrowth56.

DiscussionThe authors have referenced some of their own studies in this review. These referenced studies have been conducted in accordance with the

Table 3 Platelet protein classification and their biological roleClassification Protein Biological effectsAdhesive proteins von Willebrand factor (vWF) propeptide, fibrinogen, fibronectin, vit-

ronectin, thrombospondin 1 (TSP-1), laminin-8 (alpha4- and alpha5-laminin subunits), signal peptide-CUB-EGF domain containing protein 1 (SCUBE 1)

Cell contact interactions, ho-meostasis and clotting, and extracellular matrix compo-sition

Clotting factors and as-sociated proteins

Factor V/Va, Factor Xl-like protein, multimerin, protein S, high-molecu-lar-weight kininogen, antithrombin III, tissue factor pathway inhibitor

Thrombin production and its regulation

Fibrinolytic factors and associated proteins

Plasminogen, plasminogen activator inhibitor-1 (PAI-1), urokinase plasminogen activator (uPA), alpha2-antiplasmin, histidine-rich gly-coprotein, thrombin activatable fibrinolysis inhibitor (TAFI), alpha2-macroglobulin (2M)

Plasmin production and vas-cular modeling

Proteases and antipro-teases

Tissue inhibitor of metalloprotease 1-4 (TIMPs 1-4), metallopro-tease-1, -2, -4, -9, A disintegrin and metalloproteinase with a throm-bospondin type 1 motif, member 13 (ADAMTS13), tumor necrosis factor-alpha-converting enzyme (TACE), protease nexin-2, C1 inhibi-tor, serpin proteinase inhibitor 8, alpha1-antitrypsin

Angiogenesis, vascular modeling, regulation of co-agulation and regulation of cellular behavior

Growth factors Platelet-derived growth factor, transforming growth factor beta1 and beta2, epithelial growth factor, insulin-like growth factor type I, vascu-lar endothelial growth factor (A and C), basic fibroblastic growth fac-tor (FGF-2), hepatocyte growth factor, Bone morphogenetic protein (BMP)-2, -4, -6, connective tissue growth factor (CTGF)

Chemotaxis, cell prolifera-tion, cell differentiation and angiogenesis

Chemokines, cytokines and others

Regulated upon Activation—Normal T-cell Expressed, and Secreted (RANTES), interleukin-8 (IL-8), macrophage inflammatory protein-1 (MIP-1) alpha, epithelial neutrophil-activating peptide 78 (ENA-78), monocyte chemotactic protein-3 (MCP-3), growth regulated oncogene-alpha (GRO-alpha), angiopoietin-1, IGF-1 binding protein 3 (IGF-BP3), interleukin-6 soluble receptor (IL-6sR), platelet factor 4 (PF4), beta-thromboglobulin (bTG), platelet basic protein, neutrophil-activating protein-2 (NAP-2), connective tissue-activating peptide III, high-mobility group protein 1 (HMGB1), Fas ligand (FasL), homolo-gous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus (HSV) glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes (LIGHT), tumor ne-crosis factors (TNF)-related apoptosis-inducing ligand (TRAIL), stromal cell-derived factor-1 (SDF-1) alpha, endostatin-l, osteonectin-1, bone sialoprotein

Regulation of angiogenesis, vascular modeling, cellular interactions and bone for-mation

Antimicrobial proteins Thrombocidins, defensins Bactericidal and fungicidal properties

Others Chondroitin 4-sulfate, albumin, immunoglobulins, disabled-2, sema-phorin 3A, prion protein (PrPC)

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development of membranes that con-tain antibacterial properties, which are utilized to prevent bacterial con-tamination and faster degradation rates of the membrane in contact with the epithelium and oral mucosa. Fur-thermore, surface modifications, and a combination with growth factors and bioactive molecules are also discussed.

Antibacterial propertiesIn recent years, the focus of many laboratories has been the design of membranes that have some form of antibacterial properties57. The in-corporation of metronidazole ben-zoate (MET) to the layer interfacing the epithelial tissue has been devel-oped58 to reduce the amount of an-aerobic Gram-negative bacteria such as Porphyromonas gingivalis and anaerobic spore-forming Gram-pos-itive bacilli59,60. Other investigators have also focused on the success-ful incorporation of tetracycline hydrochloride and MET into various membranes61–63. Currently, the ma-jor focus of many investigations is on the ideal release kinetics of the

antibacterial properties to the sur-rounding environment, as fabrica-tion procedures may vary between an initial “burst” release of antibacte-rial agents, whereas others are more slowly released over time as the membranes are being degraded61,64. For a detailed description of anti-bacterial membranes, Bottino et al. recently wrote an excellent article on the numerous advancements in GTR membranes from a materials’ per-spective57.

Combination of membranes with growth factorsTo date, various growth factors, cell-based approaches and use of bone grafting materials have been utilized for the treatment of the periodon-tium. One of the key factors influenc-ing wound healing is the capability to recruit mesenchymal progenitor cells to the defect site65. The local de-livery of a wide variety of growth fac-tors, such as platelet-derived growth factors (PDGF), and bone morpho-genetic proteins that are both oste-oinductive growth factors have been

utilized in dentistry and possess the capability to further stimulate cell recruitment, proliferation and dif-ferentiation66. Numerous in vitro, animal and clinical trials have dem-onstrated the advantages of these growth factors in combination with membranes67–75.

Meanwhile, the clinical use of an enamel matrix derivative (EMD; Em-dogain, Straumann AG, Basel, Swit-zerland) has been demonstrated to increase periodontal regeneration by increasing the formation of peri-odontal tissues including alveolar bone, cementum and the periodon-tal ligament76. Accordingly, an in detailed set of in vitro experiments from members in our laboratory have demonstrated that EMD is able to drastically increase osteoblast and PDL cell proliferation and differen-tiation by up-regulating markers for osteoblast differentiation such as os-teocalcin, bone sialoprotein, runx2 and collagen177. Furthermore, it is assumed that many of the regula-tory cellular events are caused by cell condensations, which increase cell–cell contact molecules responsible for cell communication such as con-nexin4378.

ConclusionThis paper reviews the basic princi-ples in membranes utilized in GTR and GBR. Much advancement has been made since the original e-PTFE membranes, and surgical procedures are no longer necessary as they partially obstruct wound healing and increase patient discomfort. Synthesis and natural biomaterials have now been utilized in dentistry with great clinical success for over 20 years, and improvements are continuously being made regard-ing their mechanical properties and degradation rates. Furthermore, os-teoconductive calcium phosphates and bioactive growth factors are now being incorporated to allow better bone formation, while antimicro-bial substances aim to minimize the

Figure 2: Technical measures to fabricate PRF membranes. (a) Blood centrifugation at 2,700 rpm for 10 min generates two phases of blood. (b) From the middle portion of the vial, an autologous membrane containing growth factors can be removed and utilized.

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influence of bacterial contamination. The next generation of membranes is expected to combine more functional biomolecules projected to increase the success of GBR therapy.

AcknowledgementThis project was supported by Pro-gram for New Century Excellent Tal-ents in University (NCET-11-0414) and Excellent Youth Foundation of Hubei.

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