The importance of soft tissue condition in bone regenerative procedures to ensure long- term peri- implant health

Bone regenerative procedures have been widely proved to be a reliable treatment option to re-create the ideal pre-implant clinical conditions. Nevertheless, these techniques are not free from post-operative complications which might result in implant failure. Consequently, as demonstrated by the increasing recently published evidence, a careful pre- and intra-operative flap evaluation to ensure an ideal and hermetic tension-free wound closure is of paramount importance to successfully treat bony defects. In this respect, several surgical interventions mainly aimed to increase the amount of keratinized mucosa either to allow an optimal healing after a reconstructive procedure or to establish an optimal peri-implant soft tissue seal have been proposed. The present review summarizes the level of evidence on the surgical clinical aspects which have an impact on the soft tissue handling associated with bone reconstructive procedures and on the importance of soft tissue conditions to enhance and maintain peri-implant health in the long-term.


| INTRODUC TI ON
High aesthetic satisfaction, improved quality of life, and near natural rehabilitation of functionality have made dental implants a successful long-term treatment option for missing teeth in both partially and fully edentulous patients. [1][2][3][4][5][6] Furthermore, dental implants are characterized by high 10-year survival rates of 96.4%, 7 or 92.6% if assessed in a retrospective manner of up to 27 years. 8 Prospective implant sites are often compromised due to horizontal or vertical bony defects and/or lack of soft tissue volume or quality. In order to prepare the surgical sites to achieve an optimal outcome before implantation, soft and/or hard tissue augmentation procedures are frequently conducted. There is a high variety of site preparation techniques with respect to bone regeneration reported in literature. [9][10][11] These procedures aim to create an ideal anatomical basis for future predictable implant placement and are mostly conducted in a staged manner.
Second, there are special circumstances, which indicate a need for soft and/or hard tissue augmentation that aim to improve clinical, biological, and patient related outcomes. [12][13][14] Hard tissue augmentation -including bony contour augmentation -aim to improve the emergence profile of the prosthetic restoration or to stabilize the soft tissue contour on a long-term basis. Lack of buccal bone surrounding dental implants has been reported to be associated with decrease of soft tissue height. Benic et al. have investigated the relevance of buccal bone on mucosal level surrounding immediately placed implants. The investigators have shown that sites with intact buccal bone -achieved with guided bone regeneration (GBR) reveal clinically philological mucosal levels, whereas sites with deficient buccal bone height led to a mucosal recession of 1 mm. 15 Lateral ridge augmentation may also contribute to peri-implant health over a long-term period. A recent systematic review concludes that peri-implant soft and hard tissues have a bi-directional relationship showing that soft tissue augmentation is beneficial in terms of reducing mid-facial recession and brushing discomfort. 16 Irrespective of the specific surgical technique, basic surgical principles should be respected to achieve optimal treatment outcomes. Wound healing in bone regenerative techniques is generally challenging due to the techniques, the therapeutic outcome may depend on optimal blood supply as avascular grafting materials and barrier membranes are often utilized, which receive their nutrition by plasmatic diffusion from the flap and/or the underlying tissue. 17 In a series of review articles on the biology of periodontal wound healing, it was pointed out that optimal bone regeneration depends on three major factors [18][19][20] : space provision, that is, by means of a tissue barrier, wound stability (i.e., flap tension), and primary intention healing (i.e., blood supply of the flap). The same biologic principles could also be applied in bone regenerative procedures.
It is the aim of this narrative review article to elaborate on basic surgical principles of bone regenerative surgery (primary intention healing, wound stability) and to discuss the relevance of keratinized peri-implant mucosa and thickness of peri-implant mucosa.

| BA S IC SURG IC AL PRIN CIPLE S FOR BONE REG ENER ATIVE PRO CEDURE S
Various grafting methods have been employed for the treatment of bony defects including GBR-techniques and bone block/shelltechniques. 9 In all of these techniques, the prerequisite for a successful regenerative result is a passive (tension-free) flap closure. 21 Compared to horizontal bone augmentation, vertical GBR can be more challenging. The overall complication rate for vertical GBR is reported at 0%-45.4%, compared with 0%-24% for horizontal GBR. 22,23 More specifically, as reported by Donos et al., 24 differences in flap dehiscence/membrane exposure were detected at 16.3% of the implants treated with a collagen membrane, while a wide range from 11.1% to 25 24.4% was reported in cases where a e-PTFE membrane was used. 26 More recently, these findings have been further corroborated by other authors, who reported that the most commonly reported complication procedure was membrane exposure, ranging from 6.95% to 13.1%. 27,28 This is mainly due to the difficulty in advancing the flap to achieve primary wound closure which needs to be maintained during the initial healing period.
If primary wound closure is retained, healing by primary intention will lead to an undisturbed microenvironment during the healing period. This can only be achieved, if an optimal blood supply of the flap and its underlying tissue can be maintained and a tension-free wound adaptation is facilitated. 29 However, wound dehiscence leading to healing by secondary intention and adverse events (i.e., postoperative wound infection, graft exposure to the oral cavity) during vertical and horizontal bone regenerative procedures are often reported. 28,30 It has been documented, that in edentulous ridges, sites without membrane exposure achieved 74% more horizontal bone gain than sites with exposure. 31 The first part of this narrative review will focus on the basic biological principles such as systemic factors affecting healing, flap preparation, flap mobilization, and suturing techniques during bone regenerative procedures, while the second part will summarize the current level of evidence on the importance of the peri-implant keratinized peri-implant mucosa to ensure long-term peri-implant health.

| Patient-related factors
Bone regenerative procedures are elective interventions. Therefore, adequate compliance of the patient in performing oral hygiene measures and therefore healthy and fibrous soft tissue structures may allow precise incision and suturing. Poor oral hygiene has been demonstrated to negatively affect treatment outcomes for example in regenerative periodontal surgeries. 32 It must be assumed, particularly in cases with adjacent teeth, an adequate oral hygiene should be implemented before surgery and inflammation-free soft tissues have to be established. A second major factor jeopardizing optimal tissue healing is cigarette smoking. Cigarette smoking has been demonstrated to negatively influence treatment results in bone regenerative procedures. [33][34][35] It is therefore strongly recommended -especially in elective surgeries -to ensure optimal patient oral hygiene and to seek for alternative restorative treatment in smokers.

| Flap preparation
The design of oral surgical flaps is substantively reliant on the vascularization of the oral mucosa. Contrary to soft and hard tissue grafts, which obtain their nutrition in the early wound healing phase by plasmatic diffusion, [36][37][38] flaps are comprised of an established network of vessels. Thus, maintaining blood supply is the main concern, when planning different flap designs. First, recommendations for appropriate flap designs have been presented in a human cadaver study laying the anatomical foundation of incision planning. 38 Findings from these studies indicate that crestal incisions should be placed midline of the edentulous alveolar ridge which is covered by an avascular zone with no anastomosis crossing the alveolar ridge.
Moreover, adequate width of the flap base (i.e., trapezoidal shape) should always be planned to limit the risk of flap necrosis during the healing phase.
Second, the releasing incisions -if/when necessary -should be divergent and placed one tooth away from the surgical site, while in cases of edentulous areas despite the lack of tooth-related landmarks, the described general principles should be kept in mind.
This ensures that the borders of the bone graft used for the GBR procedure simultaneously performed with implant placement are completely embedded in the flap and tension and dislocation of the releasing incisions during flap closure are avoided. 39 Furthermore, as proved in a cadaver model, it was advocated that releasing incisions should be placed as short and medially as possible, as the main direction of supplying arteries is from posterior to anterior. 38 It has also been recommended, that the releasing incisions should be designed in a "hockey-stick" fashion, in order to establish broader flap margins and less tension when closing the releasing incisions. 40 Thirdly, flap thickness also seems to be an important factor for primary intention healing. A review article has pointed out that flaps thickness in plastic periodontal surgery of less than 0.7 mm may negatively influence flap vascularity. 41

| Flap mobilization
In order to minimize the risk of flap dehiscence, a tension-free wound closure is mandatory, in particular in cases with severe ridge defects.
Depending on the location of the bone augmentation procedure, several surgical techniques have been developed to achieve primary closure of bone augmentation sites.
For the maxilla, different releasing strategies haven been postulated for the buccal flap. A periosteal releasing incision connecting two vertical incisions is made to achieve elasticity of the flap. This releasing incision is further reinforced, until a completely tensionfree wound closure was possible 42 (Figure 2). In addition, coronally positioned palatal sliding flaps have been described to achieve a sufficient sliding position of the palatal tissue. 43 When regenerative procedures are performed in the mandible, coronally advanced lingual and buccal flaps have been widely postulated. [44][45][46][47][48] In most of these techniques for the lingual flap, a full thickness preparation is executed to the mylohyoid line and then released by blunt detachment (i.e., with a Pritchard elevator) of the insertion of mylohyoid muscle from the inner part. On the buccal side, a full-thickness flap is raised, and then the buccal flap is released holding the flap in tension with an anatomical forceps and by releasing the periosteum to a depth of approximately 1 mm apically to the muco-gingival junction and coronally to the vestibular fornix.
In short, with respect to flap mobilization, periosteal releasing incisions on the buccal and lingual flaps are recommended -in particular, on the lingual aspect a blunt preparation of the insertion of the mylohyoid muscle is recommended. Palatal sliding flaps might be used to increase tension-free wound closure in the anterior maxilla.

| Suturing technique
One of the basic premises of bone regenerative surgery is the attention to passive wound closure and, by this, wound stability over the  Figure 3). In addition, it has been described, that periosteal vertical mattress sutures using adsorbable suture material are able to firstly stabilize the barrier membrane and secondly add to a more passive wound closure using a combination of horizontal mattress sutures and superficial interrupted sutures. 53 When analyzing the healing patterns following suturing, it should be underlined that the sole act of applying a tensile force where the notch is placed initiated substantial and significant trauma 52 and that consequently the microcirculation is severely affected, jeopardizing optimal wound healing. Clinically, this implies that sutures should be kept in situ "as short as necessary as long as needed"; more in detail, several local factors should be carefully considered during the first healing phase in order to avoid the risk of standardized suture removal after 7-10 days. Indeed, if after only 1 week, sutures applied on the vertical releasing incisions might be removed, the same process is not recommended where mid-crestal incisions are performed to limit the risk of early exposure of the grafted area. 21 In conclusion, with respect to suturing techniques, a multi-layer wound closure using deep horizontal/vertical mattress sutures at least 3 mm distant from the wound margin combined with interrupted sutures to close the marginal flap areas are advocated ( Figure 4).

| IMP ORTAN CE OF THE PERI -IMPL ANT K ER ATINIZED MUCOSA FOR BONE REG ENER ATIVE PRO CEDURE S AND TO MAINTAIN PERI -IMPL ANT HE ALTH
It has been widely noted that tissue deficiencies such as horizontal and vertical bone defects are often associated to lack of soft tissue quality and quantity. 15   In addition, the second Consensus Meeting of the Osteology Foundation was devoted to the maintenance of peri-implant soft tissues; indeed, the systematic review presented by Thoma et al. 62 concluded that soft tissue grafting procedures resulted in a more favorable peri-implant health: (i) in order to gain keratinized mucosa using autogenous grafts with a greater improvement of bleeding indices and higher marginal bone levels; (ii) in order to increase MT using autogenous grafts with significantly less marginal bone loss.
From a clinical point of view, it has to be mentioned that, eventhough the application of a FGG to gain KM in posterior area is still considered the standard of care, this procedure does present some disadvantages such as a relative high patient's morbidity and that the harvested tissue undergoes significant shrinkage during the first healing phase.
More recently, Tavelli et al. 63  To reduce the risk of soft-tissue dehiscence and of exposure or infection of the area following guided bone regeneration, the patient was advised that preliminary soft-tissue augmentation would be beneficial prior to any attempt at bone regeneration. protecting the peri-implant structures still seems of paramount importance. In this regard, it may be reasonable to suggest that an absence of KM and the presence of a thin (0-2 mm) band of keratinized tissue should be considered to represent two different clinical conditions, even though they were included in the same group, in several studies. The other important factor that could explain the lack of association between paucity of KM and peri-implantitis, is that the incidence of peri-implantitis increases with time. Therefore, in order to demonstrate a possible association, we would need several longterm studies, when instead the vast majority of the research on this topic is limited to a few years of follow-up. [68][69][70] Several studies have demonstrated the use of various techniques for vertical ridge augmentation in cases of severe alveolar ridge atrophy, with the use of non-resorbable or resorbable membranes supported by a space-making device, or by the use of a titanium mesh. [71][72][73] These studies have also shown though that the use of a barrier device is a technique-sensitive procedure that is subject to surgical complications. 74 Recently, to overcome these problems, Even though there are no specific studies on this matter, it is reasonable to assume that membrane exposure, particularly during the first 4 postoperative weeks, may be higher in patients who present a very thin mucosa, and/or no keratinization and/or scar tissues. In specific circumstances, it may be indicated to optimize the quantity and the quality of the soft tissues, before hard tissue regenerative procedures are carried out.
Consequently, from a clinical point of view, it would be reasonable to advise surgical interventions aimed at re-creating ideal softtissue conditions whether prior to bone regenerative procedures or prior to final prosthesis delivery ( Figure 5).
The importance of the soft-tissue thickness flap during GBR procedures has been recently underling in a 3-year randomized controlled trial where it was found that implant sites that underwent horizontal GBR experienced more soft-tissue recession than those treated with a connective tissue graft. 76 This finding should be taken into consideration by clinicians during the decision-making process, especially in aesthetically demanding cases ( Figure 6).

| CON CLUS IONS
Based on the present level of evidence the following conclusions can be drawn: • Horizontal and vertical bone regenerative procedures are effective interventions in terms of bone formation around dental implants but are not free from post-operative complications which may have a negative impact on the clinical outcomes and on patients' morbidity.
• One of the most common complications, particularly in case of soft tissue deficiencies, is flap dehiscence with subsequent membrane or mesh exposure.
• Several surgical aspects such as flap design, tension, mobilization, and suture techniques must be taken into consideration prior to and during surgery to obtain an optimal healing.
• The presence of an adequate quantity and quality of soft-tissues play an important role in the long-term maintenance of periimplant health.

ACK N OWLED G M ENTS
Open access funding provided by Universitat Bern.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare no potential conflict of interests with respect to this study.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.