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Corresponding author: Krikor Giragosyan ( krikor.giragosyan@mu-plovdiv.bg ) © 2022 Krikor Giragosyan, Ivan Chenchev, Vasilena Ivanova, Stefan Zlatev.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Giragosyan K, Chenchev I, Ivanova V, Zlatev S (2022) Immunological response to nonresorbable barrier membranes used for guided bone regeneration and formation of pseudo periosteum: a narrative review. Folia Medica 64(1): 13-20. https://doi.org/10.3897/folmed.64.e60553
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Here we review the knowledge on the local biological immunological response (formation of “pseudo periosteum” of the host) to two types of nonresorbable membranes used in the horizontal and vertical alveolar ridge augmentation: the titanium-reinforced polytetrafluoroethylene membrane and the titanium mesh membrane. A literature search was conducted including available in vitro, in vivo, and clinical studies on cellular and molecular immunological response to these two types of nonresorbable membranes, in particular the formation of “pseudo periosteum”.
Emerging data demonstrates that despite barrier membranes being considered as bioinert, they still elicit an immunological response from the body. The outcome of this reaction is the formation of a thin fibrous capsule referred to as “pseudo periosteum”.
There are almost no biomaterials that are truly bioinert and this makes no exception for the nonresorbable membranes used in the guided bone regeneration. This iatrogenically made tissue is hypothesized to have a number of advantages and drawbacks. However, more research is needed in that area to truly understand its nature and importance to the guided bone regeneration process.
barrier membrane, biocompatibility, biomaterials, bone augmentation, bone formation, foreign body reaction, GBR, histology, immunological response, inflammation, polytetrafluoroethylene, pseudoperiosteum, PTFE, titanium mesh
Prosthetic rehabilitation of edentulous areas using osseointegrated implants has greatly improved the ability of dental practitioners to provide patients with more favourable long-term treatment options. Nevertheless, bone loss due to periodontal pathology, tumours or direct trauma to the alveolar processes of the jaws remains a major challenge for implant therapy. Moreover, the alveolar ridges are often subjected to atrophic processes, which further hinder the prosthetic rehabilitation of the patients. These factors require the use of various techniques, providing the alveolar ridges with the height and width necessary for optimal implant therapy. One of the treatment modalities used for achieving a sufficient bone volume is the guided bone regeneration (GBR).
GBR has been defined as a dental surgical procedure that uses barrier membranes to direct the growth of new bone at sites with insufficient volume or dimension of bone for proper function, aesthetics or prosthetic restoration.[
There are certain general criteria that need to be fulfilled for the use of resorbable and nonresorbable membranes[
According to the recommendations, when both horizontal and vertical augmentation is planned, the grafting material should be used in association with a cell occlusive membrane and a space maintaining device.[
The polytetrafluoroethylene (PTFE) polymer is an example of a linear fluoropolymer. A simplistic form of its structure is shown in Fig.
Formed by the polymerization of tetrafluoroethylene (TFE), the (–CF2–CF2–) groups repeat multiple thousands of times to form inert weave PTFE nodules and thin PTFE fibrils. The fundamental properties of fluoropolymers evolve from the atomic structure of fluorine and carbon and their covalent bonding. The backbone is formed of carbon-carbon and the pendant groups are carbon-fluorine, both being extremely strong bonds. The basic properties of PTFE stem from the chemical structure of the compound. PTFE has been shown to be biocompatible with the addition that it maintains its integrity during and after implantation. Moreover, Ti plates can be incorporated in the design of the PTFE membrane, further enhancing the product’s vertical space maintaining ability. Two different types of PTFE membranes are available depending on their architecture - expanded PTFE (ePTFE) and dense PTFE (dPTFE). The semi-separable ePTFE has myriads of small pores (<8 μm)[
The titanium mesh was introduced in 1969 by Boyne et al.[
The rigidity of the material also has some drawbacks. Mechanical irritation of the soft tissues may lead to their dehiscence and membrane exposure.[
For this narrative review, the literature survey was conducted using the Pub Med/Research Gate electronic database, without limiting the years of publication. Only papers written in English were included. The search was restricted to in vitro, in vivo human and animal studies that reported data on GBR, foreign body reactions to biomaterials and selected papers on material properties. Keywords based on MeSH terms as well as free text were used with the aim of identifying published in vitro and in vivo clinical studies that investigated cellular and molecular events around nonresorbable membranes during GBR. The following keywords were used in different combinations: “GBR”, “barrier membrane”, “bioinert”, “biocompatibility”, “membrane”, “materials”, “properties”, “polytetrafluoroethylene”, “PTFE”, “nonresorbable”, “mechanisms”, “reaction”, “foreign body”, “titanium”, “mesh”, “lattice”, “vertical augmentation”, ”pseudoperiosteum”, “adsorbed proteins”, “tissue response”, “biomaterials”, “fibroblasts”, “macrophages”, “cellular/molecular events”, “adherent cells”, “bone defect”, “in vivo”, “in vitro”, “histology”, “inflammation”, “bone formation”, “cytokines”, and “growth factors”.
Biocompatibility[
Along with understanding the physical, mechanical, and chemical properties of the membrane materials, it is also necessary to gain insight into their biologic response when they come into contact with the body. Placing a material in the body creates an interface that must exhibit both biological and structural stability during the lifetime of the implanted device. Many materials used in dentistry have the capacity to alter biologic activity when they are in close vicinity to living tissue.
Both types of materials used for the creation of non-resorbable membranes are stated to be bioinert which means they do not induce any adverse tissue reactions when introduced into the biological tissue. However, it has been shown that nearly every biomaterial induces an inflammatory tissue reaction, which is unique for every material depending on its combination of physical and chemical properties.[
Elimination by macrophagial phagocytosis as part of the innate immune system fails when the target is a foreign body (biomaterial). The foreign body reaction composed of macrophages and foreign body giant cells is the end-stage response of the inflammatory and wound healing responses following implantation of a medical device, prosthesis or a biomaterial.[
The current concept[
1. Protein adsorption
2. Acute inflammation
3. Chronic inflammation
4. Foreign body giant cell formation
5. Fibrosis or fibrous capsule formation
The very first stage of the implantation includes injury, following blood-material interactions. Subsequently, proteins of the blood plasma adsorb to the biomaterial surface, forming a blood based ephemeral provisional matrix of 2-5 nm.[
After the first stage of provisional matrix formation, acute and chronic inflammation occurs as is with any procedure that involves injury infliction on tissues. The degree of these events is determined by the severity of the trauma during the implantation procedure and the protein adsorption on the biomaterial’s surface. Neutrophils (polymorphonuclear leukocytes PMNs) play a key role in the events in the course of the acute inflammation. Mast cell degranulation with histamine release and fibrinogen adsorption is known to mediate acute inflammatory responses to implanted biomaterials.[
The matrix afterwards evolves into a blood clot at the tissue/material interface. Since all involved cells interact with the provisional matrix rather than the foreign body’s surface, its composition is assumed to be of major relevance for all subsequent events during the foreign body reaction in vivo.[
Macrophages are capable of secreting growth and angiogenic factors that are important in the regulation of fibro-proliferation and angiogenesis.[
When nonresorbable membranes are used for the purposes of guided bone regeneration, a coating of connective tissue is consistently found above the augmented sites. As mentioned above, it is occasionally referred to as “pseudo periosteum”. Generally, this is a dense connective soft tissue layer with low cellularity and no mineralization.[
Cucchi et al.[
Type 1: no pseudoperiosteum or a layer of soft tissue thinner than 1 mm. In this type, no histological analysis could be conducted because of the thinness of the coating.
Type 2: a regular soft tissue layer between 1 and 2 mm. The histological findings in this group were regular layer of connective tissue in which blood vessels and capillaries were detected. In some cases a small fragment of bone tissue is reported to be visible and surrounded by connective tissue composed of fibres with a multidirectional orientation.
Type 3: an irregular layer of soft tissue and/or layer thicker than 2 mm. Histological samples from this type are reported to consist of irregular bulks of connective tissue (poorly or not at all vascularized), and small fragments of bone graft used to fill the surgical site.
It is also reported that no inflammatory reaction or infiltrate was detected in any type of pseudoperiosteum.
As it was mentioned above, one of the main postulates of guided bone/tissue regeneration is the stabilization of the blood clot. Bone graft material and application of a non-resorbable membrane in the site that needs augmenting are utilized to ensure that this criterion is met. The “pseudo periosteum” further stabilizes the bone substitute by coating it with a layer of connective tissue. Because of that phenomenon the titanium mesh is labeled as a “protective matrix” rather than an “occlusive membrane”.[
Another aspect of the GBR procedure’s success is the angiogenesis, in particular, the vascularization of the graft material. It is mainly ensured by the bone marrow’s blood vessels which start creeping slowly through the fenestrations in the cortical plate. This nutrient supply is further enhanced by the addition of the fewer blood vessels in the pseudoperiosteum. It could also be hypothesized that pseudoperiosteum layer acts as a biological membrane, which prevents soft tissue in growth and compromising of the final result.
Barrier membranes suitable for GBR can be separated into two categories – resorbable and nonresorbable. Resorbable membranes are often favoured since their application does not require a second surgical procedure for the retrieval of the device. Despite that fact, some clinical situations such as vertical bone defects require the use of nonresorbable Ti and PTFE membranes because of their excellent space maintaining characteristics. Furthermore, after their use, a layer of connective tissue, which researchers call “pseudo periosteum” can be observed above the newly formed bone.[
The biocompatibility of the membrane materials has been extensively studied and the consensus is that they are bionert.[
The PTFE membranes were initially developed as a vascular graft material and are used extensively in cardiovascular surgery.[
Titanium and titanium alloys have a long history of successful use in dental and orthopedic application and its excellent biocompatibility has been well documented.[
The presence of this fibrous tissue, occasionally referred to as “pseudo periosteum” was first noted by Dahlin et al.[
In conclusion, there are little to no biomaterials that are truly bioinert and this makes no exception for the nonresorbable membranes used in GBR. The foreign body reaction they elicit is related to the formation of the so called “pseudo periosteum”. This iatrogenically made tissue is hypothesized to have a number of advantages and drawbacks, but further research is needed in that area in order to truly understand its nature and importance to the guided bone regeneration process.