d e n t a l m a t e r i a l s 3 1 ( 2 0 1 5 ) 640–647

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Key aspects on the use of bone substitutes for bone regeneration of edentulous ridges夽 Mariano Sanz ∗ , Fabio Vignoletti Faculty of Odontology, University Complutense of Madrid, Plaza Ramon y Cajal, 28040 Madrid, Spain

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Article history:

Objectives. To review the histological and clinical outcomes of the use of bone substitues

Received 24 July 2014

in different oral bone regenerative procedures: socket preservation, immediate implant

Received in revised form

placement, lateral and vertical bone augmentation.

14 March 2015

Methods. Histological animal studies and clinical trials regarding the performances of bone

Accepted 16 March 2015

substitutes, either allogenic, xenogeneic or alloplastic, have been evaluated. Different procedures examined separately and evidence-based results were provided. Results. The use of deproteinized bovine bone mineral (DBBM) seems to be effective most

Keywords:

clinical indications, due to their osteoconductivity, space maintenance characteristics and

Bone regeneration

slow resorption. The combination of Hydroxyapatite and Beta Tricalcium Phospate (HA/TCP)

Bone substitutes

has also reported similar histological evidence and clinical outcomes. The use of autogenous block grafts is still the method of choice in clinical situations in need of vertical bone augmentation. Conclusions. The use of bone substitutes is the standard of therapy in current modalities of lateral bone augmentation, mainly when used in conjunction with implant placement. © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

1. Introduction: principles in bone regeneration of edentulous ridges Even though alveolar bone loss can be the result of trauma, pathology, chronic/acute infections or the consequence of severe periodontal disease, the most frequent cause of clinical deficiencies in the edentulous residual ridge is the loss of mechanical function following tooth extraction or tooth loss. This physiological bone loss after tooth extraction has been corroborated in experimental studies reporting both vertical and horizontal bone resorption [1,2], what significantly alters the three-dimensional profile of the ridge and the bone

availability for placing dental implants in order to rehabilitate the chewing function and aesthetics. In fact, once a tooth is extracted, approximately 25% of the bone volume is lost after the first year [3] and with time, these resorptive changes may progress and may account for 40–60% loss of the alveolar volume within 5 years [4]. Bone availability is the main prerequisite for safe and predictable implant placement, since an adequate amount of bone is required for attaining the functional stability of the implant needed to achieve osseointegration. Moreover, the goal of achieving adequate aesthetic outcomes requires the optimal three-dimensional position of the implant following a planned prosthetic reconstruction. The presence of residual

夽 This paper was originally intended for publication with the set of papers from the Academy of Dental Materials Annual Meeting, 8–11 October 2014, Bologna, Italy; published in DENTAL 31/1 (2015). ∗ Corresponding author. E-mail addresses: [email protected] (M. Sanz), [email protected] (F. Vignoletti).

http://dx.doi.org/10.1016/j.dental.2015.03.005 0109-5641/© 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

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ridge deficiencies, both in horizontal and vertical dimensions, will influence this ideal implant position and hence, it will demand undertaking bone augmentation procedures, either concomitant with implant placement or as a staged intervention. These crestal changes may be different depending on the region of the affected jaw and similarly, the functional and aesthetic demands of the patient may vary, what advocates for an individual assessment of the possible need of bone augmentation procedures and therefore, the available bone crest must be carefully evaluated clinically and mainly through a threedimensional radiographic evaluation of the affected jaws. Alveolar crest defects have been classified in three categories, according to Seibert [5]: • Class 1 defect, when the bone deficiency is predominantly in the horizontal dimension. • Class 2 defect, when the bone deficiency is predominantly in the vertical dimension. • Class 3 defect, when the bone deficiency affects both the vertical and horizontal dimensions. A careful diagnosis of the residual alveolar ridge is fundamental in the selection of the appropriate regenerative strategy and technology, although any bone augmentation therapy must be based in a set of fundamental biological principles of wound healing, including: the promotion of primary wound closure, the enhancing of cell delivery and differentiation and the protection of the initial would stability and integrity. Primary closure is needed to assure an undisturbed environment for healing and this must be assured by appropriate flap suturing, what requires an adequate amount of soft tissue that must always be present before any regenerative surgery. The resulting flap must cover the regenerated area and when sutured it should be relatively passive and tension-free [4,6]. Proper cell proliferation and differentiation are also fundamental in the wound healing process in order to provide the angiogenic and osteogenic cells needed for bone regeneration. The main sources of osteogenic cells include the periosteum and endosteum from the walls of the bone defects, as well as the bone marrow. These cells include osteoblasts and undifferentiated mesenchymal cells, which can be differentiated into osteoblasts in presence of the adequate signalling molecules, nutrients and growth factors. This process requires adequate blood supply for providing not only oxygen and nutrients, but also as a source of mesenchymal cells. Another key factor that affects the wound healing is the stability of the blood clot. This is important because the clot promotes the formation of granulation tissue, which subsequently transforms into bone. Moreover, the clot contains a myriad of cytokines (e.g., interleukin (IL)-1, IL-8, tumor necrosis factor), growth factors (e.g., platelet-derived growth factor (PDGF), insulin-like growth factor-I (IGF-1), fibroblast growth factor-2 (FGF-2)) and signalling molecules that aid in recruiting cells to promote angiogenesis and bone regeneration [7,8]. In most clinical situations this clot stability can only be assured when physical space is provided through the use of a scaffold and the exclusion of the ingrowth of epithelial and connective tissue cells from the mucosal flap is assured by the placement of a barrier membrane [4].

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The rationale behind any crestal bone augmentation procedure is not only to establish sufficient bone availability for the safe and predictable placement of a dental implant, but also to provide adequate bone thickness around the installed implant. In fact, the influence of bone thickness around an implant has been evaluated both short and long term. During the second stage uncovering surgeries, thicknesses ≤1.5 were frequently associated with bone loss and dehiscence (exposed implant surface), while as the bone thickness approached 1.8–2 mm, the occurrence of dehiscence decreased significantly [9]. Although the “adequate” bone thickness may vary depending on the macroscopic and microscopic implant configurations, as well as in the clinical indication, it is generally agreed that at least 2 mm of bone on the buccal side of the implant are needed to achieve long term stability of periimplant soft tissues and hence, to attain adequate aesthetic outcomes. The long-term influence of bone thickness has been assessed by the occurrence of biological complications since it is expected that exposed rough implant surfaces to the oral environment may pose a higher risk of accumulating bacterial plaque biofilms and hence to develop mucosal inflammation [10]. Schwarz et al. [11], evaluated the influence of residual marginal dehiscence bone defects after guided bone regeneration on the long-term stability of peri-implant health and reported that implants exhibiting residual defect height values >1 mm were at higher risks of presenting mucosal clinical attachment loss, marginal recession and deepened probing pocket depths 4 years after treatment. In bone augmentation procedures of the residual alveolar crest the treatment strategy may include the placement of an implant and the bone augmentation procedure during the same surgical intervention (one-step procedure) or the delay of implant placement until enough bone volume has been augmented (staged procedure). The one-step procedure is indicated in class 1 defects when there is enough vertical bone for placing an implant with appropriate primary stability and the bone regenerative procedure is intended for lateral bone augmentation. In class 2 and 3 defects, depending on the amount of vertical augmentation needed the staged procedure is usually indicated. Bone augmentation procedures could also be considered when placing implants in fresh extraction sockets. In most of these clinical situations the morphology of the socket does not match with the implant diameter and depending on the resulting bone defect a bone augmentation procedure might be indicated. In this clinical indication, the timing of the bone augmentation procedure is also a determining factor, since depending on the time elapsed from tooth extraction, different soft tissue conditions may be encountered. In the mid 1980s, the Guided Tissue Regeneration (GTR) [12] [12] principle was applied in periodontal regeneration, based on the early studies of Melcher et al. [13] who developed the concept of using barrier membranes to “guide” the biological process of wound healing. These early experimental studies demonstrated that the exclusion of soft tissue invasion of the defect by means of a barrier membrane, allowed the colonization of cells with regenerative potential (derived from the periodontal ligament or bone marrow) and promoted periodontal regeneration [14]. Based on the same biological principles the Guided Bone Regeneration (GBR) treatment

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concept was developed by mechanical exclusion of the soft tissues from filling the osseous defect, and thus allowing the cells with osteogenic potential to colonize the wound [15]. Dahlin et al. [16] were the first to provide evidence to support the effectiveness of GBR around of implants inserted in rabbit tibiae. E-PTFE membranes were applied around exposed implant threads and peri-implant bone formation was formed provided enough space was secured under the membrane. Becker and Becker [17] also assessed the GBR potential to treat exposed threads of implants placed in dog mandibles. They reported a mean increase of 1.37 mm in bone height for the GBR-treated test sites, vs. 0.23 mm for the sham operated controls. Different types of barrier membranes have been tested for GBR. Their specific composition falls into two broad categories: non-resorbable and resorbable. Non-resorbable e-PTFE membranes have been frequently used in bone regeneration clinical applications, mainly with reinforced titanium strips, thus providing space-making capacity for allowing bone regeneration. However, the need of a second surgical intervention for their removal and the frequent occurrence of postoperative complications, mainly early membrane exposure, has limited their clinical use, resulting in the much broader use of biodegradable membranes. These bio-resorbable membranes must, however, ensure that the process of membrane resorption or biodegradation does not lead to tissue reactions that may affect the outcome of bone regeneration [18]. Resorbable membranes are either natural (xenogeneic collagen type I or III), which undergo resorption by enzymatic degradation, or made of synthetic polymers, including polyurethane, polyglactin 910, polylactic acid, polyglycolic acid, polyorthoester, polyethylene glycol and different combinations of polylactic and polyglycolic acid [19–22], which, when inserted in an aqueous environment, undergo enzymatic degradation by hydrolysis. With resorbable membranes the barrier function duration is variable since membrane degradation depends on many factors, such as the membrane composition, pH, temperature, the polymer crystallization degree, the cross-linking in collagen membranes and, therefore, these resorptive processes may vary and interfere with the wound healing and bone regenerative outcome [23,24]. Moreover, due to the lack of stiffness and space making properties of bioresorbable membranes, they will collapse into the bone defect or onto the implant threads under the tension of the flap and thus, the space available for bone regeneration will be occluded. Since crestal defects are usually non-contained defects, the use of a scaffold with either particulated or a block bone replacement graft is a prerequisite for both lateral or vertical bone augmentation procedures.

2.

Autogenous bone grafts

Different biomaterials, natural and/or synthetic have been developed, investigated and used as bone replacement grafts in bone augmentation procedures. Autogenous bone grafts (autografts) have been historically the gold standard in alveolar bone regenerative therapies due to their well-documented osteoconductive, osteoinductive and osteogenic properties [25,26]. Their major limitations, however, are the morbidity

and complications related to the donor site, the limited graft availability and their fast resorption rate, which requires early implant placement to provide functional loading to the regenerated bone and thus preventing its resorption [27–33]. Particulate bone grafts are usually harvested from intra-oral sites and used in combination with barrier membranes following the principles of guided bone regeneration. Mono-cortical block autografts are indicated in large crestal defects, where there is a need for vertical bone augmentation, due to their excellent space maintenance properties. These autogenous grafts may be harvested from intra or extra-oral sites. Common intra-oral donor sites are the mandibular chin or the ascending ramus area, whereas common extra-oral donor sites are the iliac crest or the calotte. They may be used alone or in combination with barrier membranes and they require fixation to the recipient crestal site with mini-screws to avoid micro-movements during healing. Their main disadvantage is the morbidity associated with their harvesting and similar to particulate autografts, their resorption rate is high. To overcome these shortcomings, the use of bone graft substitutes alone or in combination with autogenous bone grafts has become the standard treatment in bone augmentation procedures.

3.

Bone substitutes

Bone substitutes are commercially available replacement grafts used for bone regeneration in periodontology and oral and maxilla-facial surgery. They must fulfil the following requirements: biocompatibility, osteoconductivity, adequate mechanical support to provide the volume for the regenerated bone, biodegradability, and replacement by the patient’s own bone [34–36], although recent studies have suggested that a slow degradation or even non-resorption may be advantageous for the maintenance of the augmented volume [37,38]. Depending on their origin, bone substitutes are classified in three groups: Allografts, from human origin; xenografts, from another species, usually bovine or equine; and alloplasts, which are synthetically produced. Allografts are bone grafts harvested from cadaver donors and processed by freezing or demineralizing and then sterilized and supplied by specially licensed tissue banks as bone particles or blocks. Allografts include fresh-frozen bone (FFB), freeze-dried bone (FDB) and demineralized freeze-dried bone (DFDB). Their main limitation is the potential risk of cross-infection or immunologic reactions due to their protein content [39], what cannot exclude the possibility of disease transmission, although there are no reported cases from the use of DFDBA for dental purposes in over 1 million cases over 25 years [40]. Demineralized freeze-dried bone allografts (DFDBA) have shown osteoconductive, as well as osteoinductive properties, due to the release of bone morphogenetic proteins (BMPs) during the demineralization process. Although these osteonductive properties may be an advantage, comparative studies using either FDBA or DFDBA have reported similar outcomes in ridge preservation models [41]. The clinical use of these allografts is usually in combination with barrier membranes following the principles of guided bone regeneration.

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Xenografts are graft biomaterials of animal origin, mainly bovine and equine. These grafts materials are usually deproteinized by means of a chemical or low heat process, what preserves the original bone architecture and the inorganic mineral bone composition, but removes the organic component what prevents the possibility of inmmunogenic reactions. Anorganic bovine bone grafts (ABBG) or de-proteinized bovine bone mineral (DBBM) have shown good biocompatibility and osteoconductivity in preclinical studies when used following the principles of GBR, as porous particulate granules combined with a resorbable collagen barrier membrane. Moreover, these xenogeneic grafts have shown a very slow resorption rate what assures their long-term stability. In fact, whether DBBM is completely bio-bioresorbable is still a matter of controversy [35,42,43]. The presence of cells with osteoclastic characteristics has been interpreted as a sign of progressive resorption [44], although DBBM particles have been identified in long-term specimens both in humans and in experimental animals. In a recent clinical study on 20 patients evaluated 11 years after sinus floor augmentation, unchanged DBBM particles were identified integrated with the regenerated bone [42]. In a histological study in humans using DBBM granules for socket preservation, the specimens were analyzed in the coronal, mid, and apical third of the residual crest at 9 months. The average amount of vital bone ranged from 26.4 to 35.1% with most vital bone present in the apical portions and the least present in the coronal portion, where the content was mostly connective tissue (63.9%). The DBBM graft material was present uniformly throughout the socket, averaging as 30% of the socket content [45]. Another human histological study using the same experimental model compared DBBM with irradiated cancellous allograft (ICA) and to solvent-dehydrated allograft (SDA). After 4–6 months the DBBM particles that were still mostly in intimate contact with cortical bone with minimal inflammatory cell infiltrate and without evidence of fibrous encapsulation [46]. Alloplastic bone substitutes are synthetic bone substitutes that include different combinations of calcium phosphates, bioactive glasses, and polymers fabricated under different manufacturing and sintering conditions, hence resulting a in different physical properties and resorption rates. Hydroxyapatite (HA) constitutes the main mineral component of the natural bone and it is the least soluble of the naturally occurring calcium phosphate salts, what provides an osteoconductive scaffolding function, being highly resistant to physiologic resorption [47]. In contrast, tricalcium phosphate (TCP) is characterized by rapid resorption and replacement by host tissue during the early phases of healing [37,48].

filled with autografts showed similar characteristics as those sockets without any filling. Similarly, beta tricalcium phosphate alloplast (b-TCP) demonstrated limited bone promotion properties, with the graft particles being encapsulated with connective tissue [50]. In contrast, the use of xenografts (DBBM) with a much slower resorption rate, demonstrated significantly better preservation of the socket walls than the non-grafted sites. Histologically, these xenograft granules were integrated and fully surrounded by newly formed bone [51]. In clinical studies evaluating the radiographic changes of the residual crest after using different biomaterials for ridge preservation, the application of DBBM-C resulted in less vertical and horizontal changes of the alveolar ridge as compared with beta tricalcium phosphate or spontaneous healing [52]. The efficacy of HA/TCP and DBBM when used in conjunction with collagen membranes in socket preservation therapies was evaluated in a clinical trial demonstrating similar outcomes after 8 months [53]. Preclinical studies using different experimental models have also provided histological evidence that particulate or in situ hardened HA/TCP have osteoconductive properties similar to DBBM [38,54–56]. For bone defects requiring manly horizontal bone augmentation, the use of xenografts and alloplast in combination with barrier membranes has also demonstrated good results. Experimental studies testing biphasic hydroxyapatite + beta tricalcium phosphate (HA/TCP) or deproteinized bovine bone mineral (DBBM) showed significant bone fill providing an osteoconductive scaffold to support GBR procedures at dehiscence-type defects [57]. In large crestal defects aiming for both lateral and vertical bone augmentation the use of mono-cortical autogenous cortico-cancellous block grafts is the standard of therapy. In experimental studies comparing the use of this block grafts with and without a barrier membrane, a significant bucco-crestal resorption and limited bone augmentation was demonstrated in the non-membrane protected group, thus demonstrating the clear indication of always protecting the block graft with a resorbable barrier device [58]. Also in other clinical indications, such as in grafting of the maxillary sinus, HA/TCP rendered similar amounts of newly formed bone, when compared with DBBM [59,60].

4.

5.1.

Clinical indications of bone substitutes

The choice of the biomaterial should be based on the clinical indication. When the objective is to preserve the socket walls after tooth extraction, experimental studies have evaluated the histological healing when the sockets are filled with different graft materials. The use of autogenous bone chips alone does not counteract the physiologic process of bone remodeling that occurs at the socket bone walls after tooth extraction [49]. Indeed, the healing process at these sites

5.

Evidence-based results

Different systematic reviews have evaluated the efficacy of these bone substitutes when used in different clinical indications.

Ridge preservation therapies

A recent systematic review assessed the hard and soft tissue changes that occurred 6 months after tooth extraction in humans demonstrating a horizontal bone loss of 29–63% and vertical bone loss of 11–22% of the initial dimension of the alveolar bone crest at the time of extraction. Indeed, the reduction of the alveolar ridge was on average 3.87 (0.82) mm and 0.64 (0.19) in the horizontal and vertical direction, respectively [61].

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With the goal of preventing these physiologic hard and soft tissue changes ridge preservation therapies defined as “any therapeutic approach carried out immediately after tooth extraction aimed to preserve the alveolar socket architecture and to provide the maximum bone availability for implant placement” [62] were introduced and tested. Several systematic reviews have evaluated the efficacy of these interventions concluding that the use of bone substitutes to counteract the alveolar ridge dimensional changes occurring after tooth extraction, are efficient to reduce vertical and horizontal dimensional changes of the residual alveolar ridge, although are they unable to fully prevent bone resorption [62–65]. In this clinical indication, there is no evidence that the use of one bone substitute is better than other, although there are clear indications that the best outcomes are obtained when the healing occurs with the opening of the socket sealed, either by a flap, a membrane or a soft tissue graft [62]. Similarly, there is no evidence on the cost-effectiveness, patients’ preference or changes in the quality of life following socket preservation therapies. One of the main shortcomings of these interventions is to understand whether a difference in bone loss of 2–3 mm may have a significant impact on the long-term survival and success rates of the future implant supported dental restorations.

5.2.

Immediate implants at fresh extraction sockets

Different clinical studies have clearly demonstrated that implant placement in fresh extraction sockets does not counteract the physiologic bone remodeling in the alveolar bone crest and hence, vertical and horizontal dimensional changes of the alveolar crest may be expected [66,67]. In fact, a systematic review evaluating the hard and soft tissue changes after immediate implants reported that 20% of patients suffered from suboptimal aesthetic outcomes due to buccal soft tissue recession [68]. An intervention proposed to counteract these changes is the use of bone substitutes in conjunction with immediate implant placement. Results from a clinical trial showed that the use of DBBM alone or in combination with a resorbable collagen membrane reduced the horizontal resorption of the buccal bony plate by 25% when compared with the non-grafted controls [69]. The efficacy of this intervention has been evaluated in a recent systematic review reporting that the placement of a bone substitute (DBBM) to fill the gap between the socket bone walls and the implant surface, when used either alone or in combination with a collagen membrane or a connective tissue graft, resulted in a more stable peri-implant mucosa and improved aesthetic outcomes [70]. In spite of these results, data from two radiographic studies [71,72] have reported diminished bone thickness and increased mucosal recession even when peri-implant defects were grafted with DBBM, what indicates that the facial cortical bone plate continues to resorb even in the presence of the bone substitute, although the use of this low-resorption xenograft may be justified to improve the aesthetic outcomes.

5.3.

Lateral bone augmentation

Lateral or Horizontal ridge augmentation interventions can be performed using particulate or block grafts with or

without barrier membranes. The use of particulate grafts together with barrier membranes (GBR) is specially indicated in conjunction with the placement of an implant in Seibert class I defects, specially when there is enough bone width to allow for good implant primary stability. A systematic review evaluating these interventions (Donos et al) reported high implant survival rates for both the staged GBR protocol (99–100%) and the one-stage ridge augmentation in conjunction with implant placement (87–95%)[73]. A more recent systematic review [74] restricted to studies assessing horizontal ridge augmentation procedures in the anterior maxilla reported opposite results with respect to staged versus simultaneous bone augmentation, with 100% success rates for one-stage, versus 96.8% for the two–stage surgical approach [74]. These studies consisted mainly of case series using different bone replacement grafts. Five studies used the one-stage approach and reported horizontal bone gains assessed at the time of re-entry. The use of DBBM granules combined with a collagen membrane reported a gain of 3.6 mm [75]. The use of freeze-dried bone allograft blocks with plateled rich plasma and recombinant platelet derivative growth factor (rhPDGFBB) together with a chemically modified collagen membrane reported a mean gain of 4.5 mm [76]. Similar outcomes have been reported with the use of particulated autografts and allografts in combination with resorbable and non-resorbable membranes [77,78]. There is only data from one comparative study [79] reporting a slightly higher one year survival rate for implants placed at sites augmented with chin autogenous bone grafts (100%) versus sites augmented with DBBM and collagen membrane (93.5%). In summary, the use of bone substitutes, mainly of xenogeneic origin, together with resorbable membranes (collagen) has demonstrated good results, both in one-stage or two-stage horizontal bone augmentation techniques, with minimal patient morbidity and few postoperative complications. Moreover, these xenogeneic grafts have a very slow resorption rate what assures their long-term stability.

5.4.

Vertical bone augmentation

A systematic review evaluated histological and long-term outcomes of implants placed in vertically regenerated bone. This report highlighted the lack of clinical trials, the heterogeneity of the studies and the small sample sizes of most, what did not allow performing any meta-analysis. These authors concluded that there is clinical and histological evidence corroborating that vertical ridge augmentation may be achieved successfully, although the included studies reported complication rates between 0 and 45.5%, mainly related to membrane exposure and the morbidity associated with the donor site, when using autogenous bone grafts. Although the use of bone substitutes for this clinical indication is scarce, two clinical trials have compared their use in this indication versus autogenous bone blocks [80]. The comparision of DBBM bone blocks with autogenous bone blocks retrieved from the iliac crest reported similar outcomes in terms of bone regeneration with clear and significant patient preferences for the use of the bone substitute [81]. Another split-mouth pilot study [82], including only five patients, compared a malleable bone substitute

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(Regenaform® ) with particulate autogenous bone for vertical GBR at posterior mandibles with both techniques behaving similarly.

6.

[6]

Future trends [7]

The use of bio-engineering approaches where bone substitutes are used as scaffolds and are combined with either growth factors or cell therapies has attracted important attention recently and although few, there are studies showing promising results. A recent systematic review [83] evaluated the clinical outcomes with the use of cell-therapy based regenerative surgical procedures. Twenty-nine studies were identified where cell therapies were used in different indications (sinus lift, ridge preservation, ridge augmentation and regeneration of large bone defects). The cells used were mostly bone marrow-derived MSCs, although MSCs from the periosteum or adipose tissue are gaining popularity due to a more friendly harvesting procedure. In general, most studies showed similar results when cell therapy was compared with a conventional grafting technique. Only two studies compared the same scaffold material with and without cell enhancement. Gonshor et al. [84] concluded that the sinuses treated with allograft loaded with cells had a higher vital bone content and lower residual graft content than sinuses treated with conventional allograft. Hermund et al. [85] found no significant improvement in bone formation when comparing sinuses treated with ABG + BBM and sinuses treated with ABG + BBM + MSCs. In summary, the use of MSCs is a novel option in reconstructive surgery, but there is no reliable evidence suggesting which cell source and/or scaffold are the most effective and predictable for bone regeneration. Similarly, there are innovative initiatives with novel technologies for scaffold technology using nanoparticles or micro-porous structures that have shown in experimental studies the ability to enhance cell adhesion and polarization, thus promoting new bone formation [86,87]. These results, however, must be translated in adequately designed human clinical trials.

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