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.

Review

 
Oral Surgery & Medicine

Membranes for guided tissue and bone regeneration

Y Zhang*, X Zhang, B Shi, RJ Miron
 

Authors affiliations

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.

* Corresponding author Email: zyf@whu.edu.cn

Abstract

Introduction

Since the clinical use of dental membranes in the mid-1980s, guided bone regeneration procedures have become the standard in dental surgeries requiring space provision. A number of advancements have been made over the past 20 years in terms of their fabrication development. This review paper discusses original polytetrafluoroethylene non-resorbable membranes and the more recently employed innovative techniques to alter resorption periods in resorbable membranes. Furthermore, insight into future developments in membrane fabrication as well as platelet-rich fibrin membranes are discussed that will direct the next generation of guided bone regeneration.

Conclusion

There have been major advancements since the original expanded polytetrafluoroethylene membranes. Surgical procedures are no longer necessary as they cause discomfort to patients. Synthesis and natural biomaterials have been used in dentistry successfully for over 20 years, and their mechanical properties and degradation rates are being improved constantly. Furthermore, osteoconductive calcium phosphates and bioactive growth factors are now being incorporated to allow better bone formation.

Introduction

Principle of guided tissue and bone regeneration—its origin

It was not always believed that the periodontal ligament cells were responsible for the healing capabilities in the periodontium[1]. 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 bone[2]. It was not until the late 1980s and conclusively at the beginning of the 1990s following a series of experiments in monkeys that conclusive evidence supported that progenitor cells in the periodontium were from the periodontal ligament tissue[3,4,5].

Based on these results, it was hypothesized that in order to optimize regeneration, if cells derived from the periodontal ligament and alveolar 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 introduced[6]. The development of “guided tissue regeneration” (GTR) was created in order to selectively guide tissue regeneration in the periodontium following periodontal disease. Following flap surgery in monkeys exposed to plaque for 6 months, a cellulose acetate laboratory filter or expanded polytetrafluoroethylene [ePTFE]) was used to successfully prevent gingival connective tissue from contacting the root surface during healing and to produce a space for tissue ingrowth of the periodontal ligament[6]. Following 3 months of healing, it was concluded by histological evaluation that the test membranes protested from epithelial down growth exhibited considerably more new attachment and bone regrowth[6]. The results from this study confirmed the hypothesis that by selectively controlling the proliferation of the periodontal ligament cells and preventing contact from epithelium and connective tissues, the space-maintaining capability allowed for increased regeneration 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 defect[7]. The work from the above-mentioned authors has been confirmed and reproduced in a number of animal and clinical studies increasing various periodontal defects including intrabony, furcation recession and supra-alveolar defects[8,9,10,11]. Various approaches to increase new tissue and promote bone regeneration have been developed and compared (Table 1). The principles and limitations of each method suggest that GBR procedures are a better solution to non-membrane supported healing. This paper discusses the membranes used for guided tissue and bone regeneration.

Table 1

Different approaches to encourage bone regeneration

Membranes for guided tissue and bone regeneration

The very first application of a membrane providing evidence that GTR could enhance regeneration of the human periodontium was a cellulose acetate laboratory filter by Millipore[12]. Since then, a wide range of new membranes has been designed for various clinical scenarios, each possessing distinct advantages and disadvantages. As a medical application in dental implantology, barrier membranes should fulfil some fundamental requirements:

• Biocompatibility––the interaction between membranes and host tissue should not induce adverse effect;

• Space-making––the ability to maintain a space for cells from surrounding bone tissue to migrate for stable time duration;

• Cell-occlusiveness––prevention of fibrous tissue that delay bone formation from invading the defect site;

• Mechanical strength––proper physical properties to allow and protect the healing process, including protection of the underlying blood clot;

• Degradability––adequate degradation time matching the regeneration 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 2

Classification of different membranes in GBR

Non-resorbable membranes

Non-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 configurations and human histological data after treatment of intrabony lesions with ePTFE membranes demonstrate higher levels with clinical attachment level (CAL) gain and residual probing depth[14], the requirement of a second surgical intervention to remove the barrier 4 to 6 weeks after implantation is a significant drawback[15]. The need for a second surgery may injure and/or compromise the obtained regenerated tissue, since it is known that flap elevation results in a certain amount of crestal resorption of the alveolar bone[15]. Furthermore, the use of non-resorbable membranes involves extra surgical times, which leads to increased costs and patient discomfort. These undesirable characteristics are often weighed with the positive effects of using non-resorbable membrane which include effective biocompatibility and ability to maintain sufficient space in the membrane for longer periods when compared to resorbable membranes. They have a more predictable profile during the healing process for their adequate mechanical strength, and they are easy to handle in clinics[16].

PTFE membrane

PTFE membranes were first introduced to dentistry in 1984; however, the membranes had been used clinically for some previous years as a vascular graft material for hernia repair[17,18]. Both sides of the porous structure of e-PTFE have their own features[19]: on one side, an open microstructure 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% porous membrane provides space for new bone growth and acts to prevent fibrous ingrowth. The average healing 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 mucosa[20]. Compared with the conventional e-PTFE, d-PTFE demonstrates obvious advantages as they prevent infections and easy operation for removal (Table 2).

Titanium mesh

Titanium-reinforced barrier membranes 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, stability and plasticity make Ti-mesh an ideal alternative for e-PTFE products as non-resorbable membranes[21]. Rakhmatia et al. demonstrated that there are four main advantages of Ti-mesh membranes over their alternative PTFE membranes: (1) rigidity provides extensive space maintenance and prevents contour collapse; (2) elasticity prevents mucosal compression; (3) its stability prevents graft displacement and (4) plasticity permits bending, contouring 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 surgery to remove them.

Resorbable membranes

The advantage of resorbable membranes 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 unpredictable resorption time and the degree of degradation, which directly affects bone formation[22]. The ideal membrane should be capable of being degraded or resorbed over time at the same rate that bone formation occurs. A list of studies describing resorption rates is given in Table 2[23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46].

Synthetic resorbable membranes

This series of resorbable membranes mainly consist of polyesters [e.g., poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly (ε-caprolactone) (PCL)] and their co-polymers[47]. Collagen and aliphatic 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). Polyglycolide 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 physical, chemical and mechanical properties. Interestingly, the resorption of various membranes occurs via different pathways. In a review paper on this subject[48], Tatakis et al. describe that a large majority of collagen membranes is resorbed by enzymatic activity of infiltrating macrophages and polymorphonuclear leucocytes, while polymers are typically degraded through hydrolysis and the degradation products are metabolized through the citric acid cycle.

Membranes based on natural materials

The highest number of reported clinical studies involves the use of biodegradable resorbable membranes from natural materials (Table 2). Membranes based on natural materials are typically 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 maintenance ability in physiological condition, high cost and possible danger of transmitting disease to humans when applying animal-derived collagen[49]. Figure 1 demonstrates a scanning electron micrograph of a highly utilized natural membrane from bovine origin commonly used in GTR and GBR procedures (BioGuide, Geistlich Pharmaceuticals, Switzerland).

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

Focus on plasma-rich proteins (PRPs) as growth factors and membranes

PRPs isolated from platelets are a source of autologous growth factors that have been used for a variety of medical applications[50,51]. The development of platelet concentrates was first described as early as 1970 as a fibrin glue and has since exploded 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 autologous modifications to fibrin glue that has been used with apparent clinical success in dentistry. This first generation of platelet concentrates contained approximately 95% platelets 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].

Table 3

Platelet protein classification and their biological role

More recently, a natural autologous membrane has been developed through platelet concentrations—that of platelet-rich fibrin (PRF)[52,53,54]. The advantages of this membrane are that they are entirely autologous and do not contain any anti-coagulants 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 revolutions per minute for 10 min in a centrifuge tube[55]. 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 layer 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 alone or combined with other bone grafts facilitating bone regrowth[56].

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.

Discussion

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

Current trends in the development of membranes

Many advancements and modifications have been made to membranes in order to improve the mechanical properties, degradation periods via cross-linking techniques and also biocompatibility. Herein, we look at the development of membranes that contain antibacterial properties, which are utilized to prevent bacterial contamination and faster degradation rates of the membrane in contact with the epithelium and oral mucosa. Furthermore, surface modifications, and a combination with growth factors and bioactive molecules are also discussed.

Antibacterial properties

In recent years, the focus of many laboratories has been the design of membranes that have some form of antibacterial properties[57]. The incorporation of metronidazole benzoate (MET) to the layer interfacing the epithelial tissue has been developed[58] to reduce the amount of anaerobic Gram-negative bacteria such as Porphyromonas gingivalis and anaerobic spore-forming Gram-positive bacilli[59,60]. Other investigators have also focused on the successful incorporation of tetracycline hydrochloride and MET into various membranes[61,62,63]. Currently, the major focus of many investigations is on the ideal release kinetics of the antibacterial properties to the surrounding environment, as fabrication procedures may vary between an initial “burst” release of antibacterial agents, whereas others are more slowly released over time as the membranes are being degraded[61,64]. For a detailed description of antibacterial membranes, Bottino et al. recently wrote an excellent article on the numerous advancements in GTR membranes from a materials’ perspective[57].

Combination of membranes with growth factors

To date, various growth factors, cell-based approaches and use of bone grafting materials have been utilized for the treatment of the periodontium. One of the key factors influencing wound healing is the capability to recruit mesenchymal progenitor cells to the defect site[65]. The local delivery of a wide variety of growth factors, such as platelet-derived growth factors (PDGF), and bone morphogenetic proteins that are both osteoinductive growth factors have been utilized in dentistry and possess the capability to further stimulate cell recruitment, proliferation and differentiation[66]. Numerous in vitro, animal and clinical trials have demonstrated the advantages of these growth factors in combination with membranes[67,68,69,70,71,72,73,74,75].

Meanwhile, the clinical use of an enamel matrix derivative (EMD; Emdogain, Straumann AG, Basel, Switzerland) has been demonstrated to increase periodontal regeneration by increasing the formation of periodontal tissues including alveolar bone, cementum and the periodontal ligament[76]. 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 differentiation by up-regulating markers for osteoblast differentiation such as osteocalcin, bone sialoprotein, runx2 and collagen1[77]. Furthermore, it is assumed that many of the regulatory cellular events are caused by cell condensations, which increase cell–cell contact molecules responsible for cell communication such as connexin43[78].

Conclusion

This paper reviews the basic principles 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 regarding their mechanical properties and degradation rates. Furthermore, osteoconductive calcium phosphates and bioactive growth factors are now being incorporated to allow better bone formation, while antimicrobial substances aim to minimize the influence of bacterial contamination. The next generation of membranes is expected to combine more functional biomolecules projected to increase the success of GBR therapy.

Acknowledgement

This project was supported by Program for New Century Excellent Talents in University (NCET-11-0414) and Excellent Youth Foundation of Hubei.

Authors contribution

All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.

Competing interests

None declared.

Conflict of interests

None declared.

A.M.E

All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

References

  • 1. Melcher AH . On the repair potential of periodontal tissues. J Periodontol 1976 May;47(5):256-60.
  • 2. Melcher AH, McCulloch CA, Cheong T, Nemeth E, Shiga A. Cells from bone synthesize cementum-like and bone-like tissue in vitro and may migrate into periodontal ligament in vivo. J Periodontal Res 1987 May;22(3):246-7.
  • 3. Karring T, Nyman S, Gottlow J, Laurell L. Development of the biological concept of guided tissue regeneration—animal and human studies. Periodontology 2000 1993 Feb;1(1):26-35.
  • 4. Buser D, Warrer K, Karring T. Formation of a periodontal ligament around titanium implants. J Periodontol 1990 Sep;61(9):597-601.
  • 5. Buser D, Warrer K, Karring T, Stich H. Titanium implants with a true periodontal ligament: an alternative to osseointegrated implants? Int J Oral Maxillofac Implants. 1990 Summer;5(2):113-6.
  • 6. Gottlow J, Nyman S, Karring T, Lindhe J. New attachment formation as the result of controlled tissue regeneration. J Clin Periodontol 1984 Sep;11(8):494-503.
  • 7. Buser D, Dula K, Belser U, Hirt HP, Berthold H. Localized ridge augmentation using guided bone regeneration. 1. Surgical procedure in the maxilla. Int J Periodontics Restorative Dent 1993;13(1):29-45.
  • 8. Sculean A, Donos N, Brecx M, Reich E, Karring T. Treatment of intrabony defects with guided tissue regeneration and enamel-matrix-proteins. An experimental study in monkeys. J Clin Periodontol 2000 Jul;27(7):466-72.
  • 9. Niederman R, Savitt ED, Heeley JD, Duckworth JE. Regeneration of furca bone using Gore-Tex periodontal material. Int J Periodontics Restorative Dent 1989;9(6):468-80.
  • 10. Gottlow J, Karring T, Nyman S. Guided tissue regeneration following treatment of recession-type defects in the monkey. J Periodontol 1990 Nov;61(11):680-5.
  • 11. Sigurdsson TJ, Hardwick R, Bogle GC, Wikesjo UM. Periodontal repair in dogs: space provision by reinforced ePTFE membranes enhances bone and cementum regeneration in large supraalveolar defects. J Periodontol 1994 Apr;65(4):350-6.
  • 12. Nyman S, Lindhe J, Karring T, Rylander H. New attachment following surgical treatment of human periodontal disease. J Clin Periodontol 1982 Jul;9(4):290-6.
  • 13. Rakhmatia YD, Ayukawa Y, Furuhashi A, Koyano K. Current barrier membranes: Titanium mesh and other membranes for guided bone regeneration in dental applications. J Prosthodont Res 2013 Jan;57(1):3-14.
  • 14. AlGhamdi AS, Ciancio SG. Guided tissue regeneration membranes for periodontal regeneration—a literature review. J Int Acad Periodont 2009 Jul;11(3):226-31.
  • 15. Pihlstrom BL, McHugh RB, Oliphant TH, Ortiz-Campos C. Comparison of surgical and nonsurgical treatment of periodontal disease. A review of current studies and additional results after 61/2 years. J Clin Periodontol 1983 Sep;10(5):524-41.
  • 16. Gentile P, Chiono V, Tonda-Turo C, Ferreira AM, Ciardelli G. Polymeric membranes for guided bone regeneration. Biotech J 2011 Oct;6(10):1187-97.
  • 17. Elliott MP, Juler GL. Comparison of Marlex mesh and microporous teflon sheets when used for hernia repair in the experimental animal. Am J Surg 1979 Mar;137(3):342-4.
  • 18. Florian A, Cohn LH, Dammin GJ, Collins JJ Jr. Small vessel replacement with gore-tex (expanded polytetrafluoroethylene). Arch Surg 1976 Mar;111(3):267-70.
  • 19. Simion M, Dahlin C, Blair K, Schenk RK. Effect of different microstructures of e-PTFE membranes on bone regeneration and soft tissue response: a histologic study in canine mandible. Clin Oral Implants Res 1999 Apr;10(2):73-84.
  • 20. Barber HD, Lignelli J, Smith BM, Bartee BK. Using a dense PTFE membrane without primary closure to achieve bone and tissue regeneration. J Oral Maxillofac Surg 2007 Apr;65(4):748-52.
  • 21. Rakhmatia YD, Ayukawa Y, Furuhashi A, Koyano K. Current barrier membranes: titanium mesh and other membranes for guided bone regeneration in dental applications. J Prosthodont Res 2013 Jan;57(1):3-14.
  • 22. Thoma DS, Halg GA, Dard MM, Seibl R, Hammerle CH, Jung RE. Evaluation of a new biodegradable membrane to prevent gingival ingrowth into mandibular bone defects in minipigs. Clin Oral Implants Res 2009 Jan;20(1):7-16.
  • 23. Zwahlen RA, Cheung LK, Zheng LW, Chow RL, Li T, Schuknecht B. Comparison of two resorbable membrane systems in bone regeneration after removal of wisdom teeth: a randomized-controlled clinical pilot study. Clin Oral Implants Res 2009 Oct;20(10):1084-91.
  • 24. Villar CC, Cochran DL. Regeneration of periodontal tissues: guided tissue regeneration. Dent Clin North Am 2010 Jan;54(1):73-92.
  • 25. Lindfors LT, Tervonen EA, Sandor GK, Ylikontiola LP. Guided bone regeneration using a titanium-reinforced ePTFE membrane and particulate autogenous bone: the effect of smoking and membrane exposure. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010 Jun;109(6):825-30.
  • 26. Barber HD, Lignelli J, Smith BM, Bartee BK. Using a dense PTFE membrane without primary closure to achieve bone and tissue regeneration. J Oral Maxillofac Surg 2007 Apr;65(4):748-52.
  • 27. Bartee BK . Evaluation of a new polytetrafluoroethylene guided tissue regeneration membrane in healing extraction sites. Compend Contin Educ Dent 1998 Dec;19(12):1256-8.
  • 28. Marouf HA, El-Guindi HM. Efficacy of high-density versus semipermeable PTFE membranes in an elderly experimental model. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000 Feb;89(2):164-70.
  • 29. Kasaj A, Reichert C, Gö tz H, Rö hrig B, Smeets R, Willershausen B. In vitro evaluation of various bioabsorbable and nonresorbable barrier membranes for guided tissue regeneration. Head Face Med 2008 Oct;422.
  • 30. Corinaldesi G, Pieri F, Sapigni L, Marchetti C. Evaluation of survival and success rates of dental implants placed at the time of or after alveolar ridge augmentation with an autogenous mandibular bone graft and titanium mesh: a 3- to 8-year retrospective study. Int J Oral Maxillofac Implants 2009 Nov-Dec;24(6):1119-28.
  • 31. Proussaefs P, Lozada J. Use of titanium mesh for staged localized alveolar ridge augmentation: clinical and histologic-histomorphometric evaluation. J Oral Implantol 2006;32(5):237-47.
  • 32. Malchiodi L, Scarano A, Quaranta M, Piattelli A. Rigid fixation by means of titanium mesh in edentulous ridge expansion for horizontal ridge augmentation in the maxilla. Int J Oral Maxillofac Implants 1998 Sep-Oct;13(5):701-5.
  • 33. von Arx T, Broggini N, Jensen SS, Bornstein MM, Schenk RK, Buser D. Membrane durability and tissue response of different bioresorbable barrier membranes: a histologic study in the rabbit calvarium. Int J Oral Maxillofac Implants 2005 Nov-Dec;20(6):843-53.
  • 34. Milella E, Ramires PA, Brescia E, La Sala G, Di Paola L, Bruno V. Physicochemical, mechanical, and biological properties of commercial membranes for GTR. J Biomed Mater Res 2001;58(4):427-35.
  • 35. Thoma DS, Halg GA, Dard MM, Seibl R, Hammerle CH, Jung RE. Evaluation of a new biodegradable membrane to prevent gingival ingrowth into mandibular bone defects in minipigs. Clin Oral Implants Res 2009 Jan;20(1):7-16.
  • 36. Hou LT, Yan JJ, Tsai AY, Lao CS, Lin SJ, Liu CM. Polymer-assisted regeneration therapy with Atrisorb barriers in human periodontal intrabony defects. J Clin Periodontol 2004 Jan;31(1):68-74.
  • 37. Bilir A, Aybar B, Tanrikulu SH, Issever H, Tuna S. Biocompatibility of different barrier membranes in cultures of human CRL 11372 osteoblast-like cells: an immunohistochemical study. Clin Oral Implants Res 2007 Feb;18(1):46-52.
  • 38. Donos N, Kostopoulos L, Karring T. Alveolar ridge augmentation using a resorbable copolymer membrane and autogenous bone grafts. An experimental study in the rat. Clin Oral Implants Res 2002 Apr;13(2):203-13.
  • 39. Shin RH, Friedrich PF, Crum BA, Bishop AT, Shin AY. Treatment of a segmental nerve defect in the rat with use of bioabsorbable synthetic nerve conduits: a comparison of commercially available conduits. J Bone Joint Surg Am 2009 Sep;91(9):2194-204.
  • 40. Anitua E, Prado R, Sá nchez M, Orive G. Platelet-rich plasma: preparation and formulation. Oper Techniq Orthop 2012;2225-32.
  • 41. Gielkens PF, Schortinghuis J, de Jong JR, Raghoebar GM, Stegenga B, Bos RR. Vivosorb, Bio-Gide, and Gore-Tex as barrier membranes in rat mandibular defects: an evaluation by microradiography and micro-CT. Clin Oral Implants Res 2008 May;19(5):516-21.
  • 42. Sela MN, Kohavi D, Krausz E, Steinberg D, Rosen G. Enzymatic degradation of collagen-guided tissue regeneration membranes by periodontal bacteria. Clin Oral Implants Res 2003 Jun;14(3):263-8.
  • 43. Ashammakhi N, Renier D, Arnaud E, Marchac D, Ninkovic M, Donaway D. Successful use of biosorb osteofixation devices in 165 cranial and maxillofacial cases: a multicenter report. J Craniofac Surg 2004 Jul;15(4):692-701.
  • 44. Duskova M, Leamerova E, Sosna B, Gojis O. Guided tissue regeneration, barrier membranes and reconstruction of the cleft maxillary alveolus. J Craniofac Surg 2006 Nov;17(6):1153-60.
  • 45. De Angelis N, Felice P, Pellegrino G, Camurati A, Gambino P, Esposito M. Guided bone regeneration with and without a bone substitute at single post-extractive implants: 1-year post-loading results from a pragmatic multicentre randomised controlled trial. Eur J Oral Implantol 2011 Winter;4(4):313-25.
  • 46. Kim YK, Kim SG, Lim SC, Lee HJ, Yun PY. A clinical study on bone formation using a demineralized bone matrix and resorbable membrane. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010 Jun;109(6):e6-11.
  • 47. Sculean A, Nikolidakis D, Schwarz F. Regeneration of periodontal tissues: combinations of barrier membranes and grafting materials—biological foundation and preclinical evidence: a systematic review. J Clin Periodontol 2008 Sep;35(8 Suppl):106-16.
  • 48. Tatakis DN, Promsudthi A, Wikesjo UM. Devices for periodontal regeneration. Periodontology 2000 1999 Feb;1959-73.
  • 49. Dori F, Huszar T, Nikolidakis D, Arweiler NB, Gera I, Sculean A. Effect of platelet-rich plasma on the healing of intra-bony defects treated with a natural bone mineral and a collagen membrane. J Clin Periodontol 2007 Mar;34(3):254-61.
  • 50. Del Corso M, Vervelle A, Simonpieri A, Jimbo R, Inchingolo F, Sammartino G. Current knowledge and perspectives for the use of platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) in oral and maxillofacial surgery part 1: Periodontal and dentoalveolar surgery. Curr Pharmaceut Biotech 2012 Jun;13(7):1207-30.
  • 51. Simonpieri A, Del Corso M, Vervelle A, Jimbo R, Inchingolo F, Sammartino G. Current knowledge and perspectives for the use of platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) in oral and maxillofacial surgery part 2: Bone graft, implant and reconstructive surgery. Curr Pharmaceut Biotech 2012 Jun;13(7):1231-56.
  • 52. Choukroun J, Diss A, Simonpieri A, Girard MO, Schoeffler C, Dohan SL. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part IV: clinical effects on tissue healing. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 Mar;101(3):e56-60.
  • 53. Dohan DM, Choukroun J, Diss A, Dohan SL, Dohan AJ, Mouhyi J. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part I: technological concepts and evolution. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 Mar;101(3):e37-44.
  • 54. Dohan DM, Choukroun J, Diss A, Dohan SL, Dohan AJ, Mouhyi J. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part II: platelet-related biologic features. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 Mar;101(3):e45-50.
  • 55. Dohan DM, Choukroun J, Diss A, Dohan SL, Dohan AJ, Mouhyi J. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part III: leucocyte activation: a new feature for platelet concentrates? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 Mar;101(3):e51-5.
  • 56. Choukroun J, Diss A, Simonpieri A, Girard MO, Schoeffler C, Dohan SL. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part V: histologic evaluations of PRF effects on bone allograft maturation in sinus lift. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 Mar;101(3):299-303.
  • 57. Bottino MC, Thomas V, Schmidt G, Vohra YK, Chu TM, Kowolik MJ. Recent advances in the development of GTR/GBR membranes for periodontal regeneration—a materials perspective. Dental Mater 2012 Jul;28(7):703-21.
  • 58. Bottino MC, Thomas V, Janowski GM. A novel spatially designed and functionally graded electrospun membrane for periodontal regeneration. Acta Biomater 2011 Jan;7(1):216-24.
  • 59. Freeman CD, Klutman NE, Lamp KC. Metronidazole. A therapeutic review and update. Drugs 1997 Nov;54(5):679-708.
  • 60. El-Kamel AH, Ashri LY, Alsarra IA. Micromatricial metronidazole benzoate film as a local mucoadhesive delivery system for treatment of periodontal diseases. AAPS PharmSciTech 2007 Sep;8(3):E75.
  • 61. He CL, Huang ZM, Han XJ. Fabrication of drug-loaded electrospun aligned fibrous threads for suture applications. J Biomed Mater Res A 2009 Apr;89(1):80-95.
  • 62. Kenawy el R, Bowlin GL, Mansfield K, Layman J, Simpson DG, Sanders EH. Release of tetracycline hydrochloride from electrospun poly(ethylene-co-vinylacetate), poly(lactic acid), and a blend. J Control Release 2002 May;81(1-2):57-64.
  • 63. Pham QP, Sharma U, Mikos AG. Electrospinning of polymeric nanofibers for tissue engineering applications: a review. Tissue Eng 2006 May;12(5):1197-211.
  • 64. Zamani M, Morshed M, Varshosaz J, Jannesari M. Controlled release of metronidazole benzoate from poly epsilon-caprolactone electrospun nanofibers for periodontal diseases. Eur J Pharma Biopharma 2010 Jun;75(2):179-85.
  • 65. Zhang Y, Cheng N, Miron R, Shi B, Cheng X. Delivery of PDGF-B and BMP-7 by mesoporous bioglass/silk fibrin scaffolds for the repair of osteoporotic defects. Biomaterials 2012 Oct;33(28):6698-708.
  • 66. Miron RJ, Zhang YF. Osteoinduction: a review of old concepts with new standards. J Dent Res 2012 Aug;91(8):736-44.
  • 67. Christgau M, Moder D, Hiller KA, Dada A, Schmitz G, Schmalz G. Growth factors and cytokines in autologous platelet concentrate and their correlation to periodontal regeneration outcomes. J Clin Periodontol 2006 Nov;33(11):837-45.
  • 68. Kaigler D, Avila G, Wisner-Lynch L, Nevins ML, Nevins M, Rasperini G. Platelet-derived growth factor applications in periodontal and peri-implant bone regeneration. Expert Opin Biol Ther 2011 Mar;11(3):375-85.
  • 69. Nevins M, Camelo M, Nevins ML, Schenk RK, Lynch SE. Periodontal regeneration in humans using recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and allogenic bone. J Periodontol 2003 Sep;74(9):1282-92.
  • 70. Nevins ML, Reynolds MA. Tissue engineering with recombinant human platelet-derived growth factor BB for implant site development. Compend Contin Educ Dent 2011 Mar;32(2):18, 20-7.
  • 71. Rosen PS, Toscano N, Holzclaw D, Reynolds MA. A retrospective consecutive case series using mineralized allograft combined with recombinant human platelet-derived growth factor BB to treat moderate to severe osseous lesions. Int J Periodontics Restorative Dent 2011 Jul-Aug;31(4):335-42.
  • 72. Miron RJ, Saulacic N, Buser D, Iizuka T, Sculean A. Osteoblast proliferation and differentiation on a barrier membrane in combination with BMP2 and TGFbeta1. Clin Oral Investig 2013 Apr;17(3):981-8.
  • 73. Jones AA, Buser D, Schenk R, Wozney J, Cochran DL. The effect of rhBMP-2 around endosseous implants with and without membranes in the canine model. J Periodontol 2006 Jul;77(7):1184-93.
  • 74. Jung RE, Glauser R, Scharer P, Hammerle CH, Sailer HF, Weber FE. Effect of rhBMP-2 on guided bone regeneration in humans. Clin Oral Implants Res 2003 Oct;14(5):556-68.
  • 75. Jung RE, Windisch SI, Eggenschwiler AM, Thoma DS, Weber FE, Hammerle CH. A randomized-controlled clinical trial evaluating clinical and radiological outcomes after 3 and 5 years of dental implants placed in bone regenerated by means of GBR techniques with or without the addition of BMP-2. Clin Oral Implants Res 2009 Jul;20(7):660-6.
  • 76. Sculean A, Alessandri R, Miron RJ, Salvi G, Bosshard DD. Enamel matrix proteins and periodontal wound healing and regeneration. Clin Adv Periodont 2011;1101-17.
  • 77. Miron RJ, Bosshardt D, Hedbom E, Zhang Y, Haenni B, Buser D. Adsorption of enamel matrix proteins to a bovine derived bone grafting material and its regulation of cell adhesion, proliferation and differentiation. J Periodontol 2012 Jul;83(7):936-47.
  • 78. Miron RJ, Hedbom E, Ruggiero S, Bosshardt DD, Zhang Y, Mauth C. Premature osteoblast clustering by enamel matrix proteins induces osteoblast differentiation through up-regulation of connexin 43 and N-cadherin. PloS one 2011;6(8):e23375.
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Different approaches to encourage bone regeneration

Approaches Principles Typical examples Limitations
Osteoconduction 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

Classification of different membranes in GBR

Membranes Commercial name Manufacturer and nation Material Properties Comments Reference
Non-resorbable membranes e-PTFE Gore-Tex W. L. Gore & Associates, Inc., USA e-PTFE Good space maintainer Easy to handle Longest clinical experience 23,24
Gore-Tex-TI W. L. Gore & Associates, Inc., USA Ti-e-PTFE Most stable space maintainer Filler material unnecessary Titanium should not be exposed Commonly 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 secondary surgery 26
Cytoplast Osteogenics Biomedical., USA <0.3 μm pores Primary closure unnecessary 27
TefGen FD Lifecore Biomedical, Inc., USA 0.2–0.3 μm pores Easy to detach 28
Non-resorbable ACE Surgical supply, Inc., USA <0.2 μm pores 0.2 mm thick Limited cell proliferation 29
Titanium mesh Ti-Micromesh ACE Surgical supply, Inc., USA Ti 1,700 mm pores 0.1 mm thick Ideal long term survival rate 30
Tocksystem Mesh Tocksystem, Italy 0.1–6.5 mm pore 0.1 mm thick Minimal resorption and inflammation 31
Frios BoneShields Dentsply Friadent, Germany 0.03 mm pores 0.1 mm thick Sufficient bone to regenerate 31
M-TAM 1,700 mm pores 0.1–0.3 mm thick Excellent tissue compatibility 32
Synthetic resorbable membranes OsseoQuest W. L. Gore & Associates, Inc., USA Hydrolyzable polyester Resorption: 16–24 weeks Good tissue integration 33
Biofix Bioscience Oy, USA Polyglycolic acid Resorption: 24–48 weeks Isolate the space from cells from soft tissue and bacteria 34
Vicryl Johnson & Johnson, USA Polyglactin 910 Polyglicolid/polyl actid 9:1 Well adaptable Resorption: 4–12 weeks Woven membrane Four prefabricated shapes 35
Atrisorb Tolmar, Inc., USA Poly-DL-lactide and solvent Resorption: 36–48 weeks Interesting resorptive characteristics Custom fabricated membrane “Barrier Kit” 36
EpiGuide Kensey Nash corporation, USA Poly-DL-lactic acid Three-layer membrane Resorption: 6–12 weeks Self-supporting Support developed blood clot 37
Resolut W. 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 properties 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 proteins mediate cell behaviors Different formulations for various usages Total resorption Enhance osseointegration and initial implant stability Promote new bone formation Encourage soft tissue recovery 40
Bio-Gide Osteohealth Company, SUI Porcine I and III Resorption: 24 weeks Mechanical strength: 7.5 MPa Usually used in combination with filler materials 41
Bio-mend Zimmer, USA Bovine I Resorption: 8 weeks Mechanical strength: 3.5–22.5 MPa Fibrous network Modulate cell activities 42
Biosorb membrane 3M ESPE, USA Bovine I Resorption: 26–38 weeks Tissue integration 43
Neomem Citagenix, CAN Bovine I Double-layer product Resorption: 26–38 weeks 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 weeks Increase the woven bone 46

Platelet protein classification and their biological role

Classification Protein Biological effects
Adhesive proteins von Willebrand factor (vWF) propeptide, fibrinogen, fibronectin, vitronectin, thrombospondin 1 (TSP-1), laminin-8 (alpha4- and alpha5-laminin subunits), signal peptide-CUB-EGF domain containing protein 1 (SCUBE 1) Cell contact interactions, homeostasis and clotting, and extracellular matrix composition
Clotting factors and associated proteins Factor V/Va, Factor Xl-like protein, multimerin, protein S, high-molecular-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 glycoprotein, thrombin activatable fibrinolysis inhibitor (TAFI), alpha2-macroglobulin (2M) Plasmin production and vascular modeling
Proteases and antiproteases Tissue inhibitor of metalloprotease 1-4 (TIMPs 1-4), metalloprotease-1, -2, -4, -9, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), tumor necrosis factor-alpha-converting enzyme (TACE), protease nexin-2, C1 inhibitor, serpin proteinase inhibitor 8, alpha1-antitrypsin Angiogenesis, vascular modeling, regulation of coagulation 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, vascular endothelial growth factor (A and C), basic fibroblastic growth factor (FGF-2), hepatocyte growth factor, Bone morphogenetic protein (BMP)-2, -4, -6, connective tissue growth factor (CTGF) Chemotaxis, cell proliferation, 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), homologous 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 necrosis 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 formation
Antimicrobial proteins Thrombocidins, defensins Bactericidal and fungicidal properties
Others Chondroitin 4-sulfate, albumin, immunoglobulins, disabled-2, semaphorin 3A, prion protein (PrPC)
Keywords