Gaia Pellegrini

Pre-clinical Models for Oral and Periodontal Reconstructive Therapies

The development of new medical formulations (NMF) for reconstructive therapies has considerably improved the available treatment options for individuals requiring periodontal repair or oral implant rehabilitation. Progress in tissue engineering and regenerative medicine modalities strongly depends on validated pre-clinical research. Pre-clinical testing has contributed to the recent approval of NMF such as GEM 21S® and INFUSE® bone grafts for periodontal and oral regenerative therapies. However, the selection of a suitable pre-clinical model for evaluation of the safety and efficacy of a NMF remains a challenge. This review is designed to serve as a primer to choose the appropriate pre-clinical models for the evaluation of NMF in situations requiring periodontal or oral reconstruction. Here, we summarize commonly used pre-clinical models and provide examples of screening and functional studies of NMF that can be translated into clinical use.

PDGF-B Gene Therapy Accelerates Bone Engineering and Oral Implant Osseointegration

Platelet-derived growth factor-BB (PDGF-BB) stimulates repair of healing-impaired chronic wounds such as diabetic ulcers and periodontal lesions. However, limitations in predictability of tissue regeneration occur due, in part, to transient growth factor bioavailability in vivo. Here, we report that gene delivery of PDGF-B stimulates repair of oral implant extraction socket defects. Alveolar ridge defects were created in rats and were treated at the time of titanium implant installation with a collagen matrix containing an adenoviral (Ad) vector encoding PDGF-B (5.5 × 108 or 5.5 × 109 pfu ml−1), Ad encoding luciferase (Ad-Luc; 5.5 × 109 pfu ml−1; control) or recombinant human PDGF-BB protein (rhPDGF-BB, 0.3 mg ml−1). Bone repair and osseointegration were measured through backscattered scanning electron microscopy, histomorphometry, micro-computed tomography and biomechanical assessments. Furthermore, a panel of local and systemic safety assessments was performed. Results indicated that bone repair was accelerated by Ad-PDGF-B and rhPDGF-BB delivery compared with Ad-Luc, with the high dose of Ad-PDGF-B more effective than the low dose. No significant dissemination of the vector construct or alteration of systemic parameters was noted. In summary, gene delivery of Ad-PDGF-B shows regenerative and safety capabilities for bone tissue engineering and osseointegration in alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo.

Postextraction Alveolar Ridge Preservation: Biological Basis and Treatments

Following tooth extraction, the alveolar ridge undergoes an inevitable remodeling process that influences implant therapy of the edentulous area. Socket grafting is a commonly adopted therapy for the preservation of alveolar bone structures in combination or not with immediate implant placement although the biological bases lying behind this treatment modality are not fully understood and often misinterpreted. This review is intended to clarify the literature support to socket grafting in order to provide practitioners with valid tools to make a conscious decision of when and why to recommend this therapy.

Soft tissues around long-term platform switching implant restorations: a histological human evaluation. Preliminary results.

BACKGROUND Switching platform restorations seems to reduce the peri-implant bone resorption and to preserve the peri-implant soft tissues. AIM The aim of the present human study was to compare histologically the peri-implant soft tissue in switching and traditional platform implants 4 years after restoration. MATERIALS AND METHODS Forty-eight months after implant restoration, 37 peri-implant soft tissue samples from 14 patients were harvested from traditionally restored implants (control group) and from three different platforms mismatching 0.25-0.85 mm (test groups). At the harvesting time, all sites were clinically healthy. Samples were processed to evaluate the inflammatory infiltrate area [inflamed connective tissue (ICT)], the microvascular density (MVD) and the collagen content (AA%). RESULTS At the analyses, no significant differences were found between groups in terms of ICT, MVD and AA% (p>0.05). In all groups, most samples with a well-preserved junctional epithelium showed a small and localized inflammatory infiltrated associated with not-well-oriented collagen fibres and an increased MVD. CONCLUSIONS Forty-eight months after restoration, switching and traditional platform implants had similar histological peri-implant soft tissue features, despite different bone level changes detected radiographically and published in a previous parent study. The present study seems to confirm platform switching as a safe prosthetic concept leading to better maintenance of peri-implant bone levels. However, further histological studies are required to longitudinally confirm the present data.

A new method to evaluate volumetric changes in sinus augmentation procedure

BACKGROUND In sinus augmentation procedure, the assessment of volume changes of grafted materials is important both in the clinical practice and in dental research to evaluate the features of filling materials. PURPOSE In this study, we assessed the repeatability of a new method proposed to evaluate volumetric changes following sinus lift augmentation procedure. MATERIALS AND METHODS In 10 patients, maxillary sinus augmentation procedure with simultaneous implant placement was performed. Maxillary cone beam computer tomographies were taken 1 week after surgery (T1) and 6 months after surgery (T2). At each evaluation the gap inside the implant between the fixture and the bottom of the screw was used as reference point (Rp), and a standardized volume of interest (VOI) centered on the Rp was selected. Masks were chosen to select the graft and bone tissue within the VOI; the volume at T1, T2, and the difference of volume between T1 and T2 were computed. Expert and non-expert operators performed the analysis. Method errors were computed. RESULTS The error of the method was 1% for both intra-operator and inter-operator measurements. Tissue contraction at T2 was 19 ± 4% of the total initial volume. CONCLUSIONS The standardization of the method allows to obtain repeatable measurements.

Surgical Approaches Based on Biological Objectives: GTR versus GBR Techniques

Guided tissue regenerative (GTR) therapies are performed to regenerate the previously lost tooth supporting structure, thus maintaining the aesthetics and masticatory function of the available dentition. Alveolar ridge augmentation procedures (GBR) intend to regain the alveolar bone lost following tooth extraction and/or periodontal disease. Several biomaterials and surgical approaches have been proposed. In this paper we report biomaterials and surgical techniques used for periodontal and bone regenerative procedures. Particular attention will be adopted to highlight the biological basis for the different therapeutic approaches.

Preclinical methods for the evaluation of periodontal regeneration in vivo.

For the determination of key factors or devices that promote periodontal regeneration, preclinical investigations using in vivo animal models are critical for evaluating the biological responses before human clinical trial testing. In this chapter, we provide an overview on the commonly used preclinical animals for the study of reconstructive procedures to promote bone and soft tissue repair of tooth-supporting periodontal defects. Steps are provided on the animal management for evaluation of outcome measures using descriptive histology, histomorphometry, three-dimensional imaging, and safety assessments. The use of these key measures of periodontal regeneration should aid investigators in the selection of appropriate surrogate endpoints to be utilized in the clinical arena, which are not practical or ethical in humans. These methods will prepare investigators and assist them in identifying endpoints that can then be adapted to human clinical trial planning.

Alveolar socket preservation technique: Effect of biomaterial on bone regenerative pattern

BACKGROUND There is a lack of evidence in the literature on the correlation between histomorphometric findings and gene/protein expression markers for bone metabolism. AIM Evaluation of the histological features, changes in protein expression and gene activation for specific markers of bone metabolism following application of the alveolar ridge preservation technique with magnesium-enriched hydroxyapatite (MgHA). MATERIALS AND METHODS For each patient (n=15), bone samples were harvested after tooth extraction and processed for immunohistochemical and gene expression analysis (T0). Then, all alveolar sockets were grafted with MgHA. After 4 months (T1), bone samples were harvested for histomorphometrical, immunohistochemical and gene expression analysis. Gene expression and protein expression were evaluated for: RANK, RANKL, OPG, IL-6, TNF-α. RESULTS For all markers, gene expression increased, but not significantly, from T0 to T1. The mean RANKL/OPG ratio was 1.88±1.24. Protein expression increased significantly (p<0.05) for TNF-α, IL-6, RANK and RANKL. Histomorphometrical features at T1 were not significantly related to protein expression at T0. CONCLUSIONS After ridge preservation with MgHA, markers for bone catabolism were activated. No significant correlation was found between histomorphometrical features of the regenerated tissue and protein expression at baseline.

Soft tissue surrounding switched platform implants: an immunohistochemical evaluation.

OBJECTIVES This clinical and immunohistochemical study was designed to characterize the cellular and molecular patterns for bone loss of soft tissues surrounding implants restored with different implant platform configurations. MATERIAL AND METHODS A total of 32 implants were restored using abutments with the following mismatches: 0 mm (control group), 0.25 mm (test group(1)), 0.5 mm (test group(2)) and 0.85 mm (test group(3)). Four years after, loading all sites were clinically healthy, and soft tissue samples were harvested and processed for immunohistochemical analysis. Amounts of lymphocytes T (LyT) -B (LyB), IL-17 and RANKL were assessed. RESULTS No significant difference was found between groups (P > 0.05) in terms of infiltrated T and B cell counts, IL-17 and RANKL expressions. When pooled data were analysed, lymphocytes T counts and IL-17 were higher than lymphocytes B counts and RANKL. LyT and LyB counts were highly negatively correlated (Pearsons r > 0.7) and IL-17 was correlated (Pearsons r > 0.4, <0.7) to LyT and LyB. CONCLUSIONS After prolonged exposure of abutments in the oral cavity, the configuration of the implant abutment interface does not seem to affect the inflammatory cellular and molecular pattern responsible for bone loss.

Histological features of peri-implant bone subjected to overload.

PURPOSE The aim of this review has been to investigate the histological findings of bone structure surrounding implants subjected to excessive load. MATERIALS AND METHODS Clinical and pre-clinical histological studies that observed overloaded intraoral implants were included. RESULTS All included studies (n=15) were conducted on animals. Most of them failed to find pathological alteration in the microstructure of bone surrounding overloaded implants. Overload and infection alone may induce bone loss, but related lesions have different and peculiar features. CONCLUSIONS The different histological features observed around implants subjected to overload or to ligature-induced peri-implantitis may indicate a specific pathogenetic mechanism for overload or infection-induced loss of osseointegration. The clinical significance of these findings should be confirmed in human studies.