Repeated Application and Removal of Polyisocyanopeptide Hydrogel Wound Dressings in a Splinted Full-Thickness Wound Model.

Polyisocyanopeptide (PIC) hydrogels are proposed as promising wound dressings. These gels are thermo-sensitive, allow application as a cold liquid, and rely on gelation through body heat. It is supposed that the gel can be easily removed by reversing the gelation and washing it away with a cold irrigation solution. The impact on wound healing of the regular application and removal of PIC dressings is compared to a single application of PIC and the clinically used Tegaderm™ in murine splinted full-thickness wounds for up to 14 days. SPECT/CT analysis of 111In-labelled PIC gels showed that, on average, 58% of the PIC gel could be washed out of the wounds with the employed method, which is, however, heavily influenced by personal technique. Evaluation with photography and (immuno-)histology showed that wounds in which PIC dressings were regularly removed and replaced were smaller at 14 days post-injury but performed on par with the control treatment. Moreover, the encapsulation of PIC in wound tissue was less severe and occurred less often when PIC was regularly refreshed. In addition, no morphological damage related to the removal procedure was observed. Thus, PIC gels are atraumatic and perform similarly to currently employed wound dressing materials, offering possible future benefits for both clinicians and patients.

Biomaterials-aided mandibular reconstruction using in vivo bioreactors.

Large mandibular defects are clinically challenging to reconstruct due to the complex anatomy of the jaw and the limited availability of appropriate tissue for repair. We envision leveraging current advances in fabrication and biomaterials to create implantable devices that generate bone within the patients themselves suitable for their own specific anatomical pathology. The in vivo bioreactor strategy facilitates the generation of large autologous vascularized bony tissue of customized geometry without the addition of exogenous growth factors or cells. To translate this technology, we investigated its success in reconstructing a mandibular defect of physiologically relevant size in sheep. We fabricated and implanted 3D-printed in vivo bioreactors against rib periosteum and utilized biomaterial-based space maintenance to preserve the native anatomical mandibular structure in the defect site before reconstruction. Nine weeks after bioreactor implantation, the ovine mandibles were repaired with the autologous bony tissue generated from the in vivo bioreactors. We evaluated tissues generated in bioreactors by radiographic, histological, mechanical, and biomolecular assays and repaired mandibles by radiographic and histological assays. Biomaterial-aided mandibular reconstruction was successful in a large superior marginal defect in five of six (83%) sheep. Given that these studies utilized clinically available biomaterials, such as bone cement and ceramic particles, this strategy is designed for rapid human translation to improve outcomes in patients with large mandibular defects.

Application of specialized pro-resolving mediators in periodontitis and peri-implantitis: a review.

Scaling and root planning is a key element in the mechanical therapy used for the eradication of biofilm, which is the major etiological factor for periodontitis and peri-implantitis. However, periodontitis is also a host mediated disease, therefore, removal of the biofilm without adjunctive therapy may not achieve the desired clinical outcome due to persistent activation of the innate and adaptive immune cells. Most recently, even the resident cells of the periodontium, including periodontal ligament fibroblasts, have been shown to produce several inflammatory factors in response to bacterial challenge. With increased understanding of the pathophysiology of periodontitis, more research is focusing on opposing excessive inflammation with specialized pro-resolving mediators (SPMs). This review article covers the major limitations of current standards of care for periodontitis and peri-implantitis, and it highlights recent advances and prospects of SPMs in the context of tissue reconstruction and regeneration. Here, we focus primarily on the role of SPMs in restoring tissue homeostasis after periodontal infection.

The effect of lipoxin A4 on E. coli LPS-induced osteoclastogenesis.

OBJECTIVES: The objective of the present study was to investigate the effect of lipoxin-type A4 (LXA4) on bacterial-induced osteoclastogenesis. MATERIAL AND METHODS: Human periodontal ligament cells (PDLCs) in coculture with osteoclast precursors (RAW264.7 cells) were exposed to bacterial stimulation with lipopolysaccharide (LPS) to induce inflammation. After 24 h, cells were treated to 100 ng/ml of LXA4 and 50 ng/ml of forymul peptide receptor 2 (FPR2/ALX) receptor antagonist (Boc-2). After 5 days, osteoclastic resorptive activity was assessed on calcium phosphate (CaP) synthetic bone substitute. Additionally, osteoclastic differentiation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, TRAP enzymatic activity assay, and on the expression of osteoclast-specific genes. RESULTS: We found that stimulation of in the osteoclasts with LPS-stimulated PDLCs induced a significant increase in tartrate-resistant acid phosphatase (TRAP) positive cells, higher resorptive activity, and enhanced expression of specific genes. Meanwhile, LXA4-treatment exhibited strong anti-inflammatory activity, and was able to reverse these inflammatory effects. CONCLUSIONS: We conclude that (1) PDLCs are a potential target for treating bacterial-induced bone resorption in patients with periodontal disease, and (2) LXA4 is a suitable candidate for such therapy. CLINICAL RELEVANCE: The results prove that lipoxins have a protective role in bacterial-induced periodontal inflammation and alveolar bone resorption, which can be translated into a clinical beneficial alterative treatment.

A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia.

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (ß = -0.9, P = 4.21 × 10-21), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10-7). This genotype, also termed "Duffy-null", has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatment.

Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice.

AIMS: SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms. METHODS AND RESULTS: We assessed electrophysiological and molecular alterations underlying AV-conduction abnormalities in mice carrying the Scn5a1798insD/+ mutation. Langendorff-perfused Scn5a1798insD/+ hearts showed prolonged AV-conduction compared to wild type (WT) without changes in atrial and His-ventricular (HV) conduction. The late sodium current (INa,L) inhibitor ranolazine (RAN) normalized AV-conduction in Scn5a1798insD/+ mice, likely by preventing the mutation-induced increase in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentrations. Indeed, further enhancement of [Na+]i and [Ca2+]i by the Na+/K+-ATPase inhibitor ouabain caused excessive increase in AV-conduction time in Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ mice, in line with their larger mutation-induced INa,L. Transverse aortic constriction (TAC) caused excessive prolongation of AV-conduction in FVB/N-Scn5a1798insD/+ mice (while HV-intervals remained unchanged), which was prevented by chronic RAN treatment. Scn5a1798insD/+-TAC hearts showed decreased mRNA levels of conduction genes in the AV-nodal region, but no structural changes in the AV-node or His bundle. In Scn5a1798insD/+-TAC mice deficient for the transcription factor Nfatc2 (effector of the calcium-calcineurin pathway), AV-conduction and conduction gene expression were restored to WT levels. CONCLUSIONS: Our findings indicate a detrimental role for enhanced INa,L and consequent calcium dysregulation on AV-conduction in Scn5a1798insD/+ mice, providing evidence for a functional mechanism underlying AV-conduction disturbances secondary to gain-of-function SCN5A mutations.

Lipoxin suppresses inflammation via the TLR4/MyD88/NF-κB pathway in periodontal ligament cells.

OBJECTIVE: The objective of the present study was to evaluate the anti-inflammatory effects of lipoxin A4 (LXA4) for the treatment of periodontitis in an in vitro model. METHODS: Human PDLCs were challenged with Escherichia coli (E. coli) lipopolysaccharide (LPS) to evoke an inflammatory response. This was done either in monoculture or in coculture with THP-1, a monocytic cell line. Thereafter, cytokine expression was measured by ELISA, with or without LXA4. In addition, the effects of LXA4 were analyzed on the TLR-MyD88-NF-κB (TMN)-mediated intracellular signal pathway using immunocytochemistry. RESULTS: In response to LPS, the level of the pro-inflammatory cytokine tumor necrosis factor alpha increased, whereas the anti-inflammatory cytokine interleukin-4 decreased significantly (p < .05). These effects were consistently reversed when LPS-challenged PDLCs were also treated with LXA4. The results in the coculture system were comparable to the monoculture. Immunohistochemistry and quantitative assessment confirmed the importance of the TMN signal pathway in these processes. CONCLUSION: These results corroborate earlier findings that PDLCs play an important role in inflammation. Moreover, LXA4 might offer new approaches for the therapeutic treatment of periodontal disease.

A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy.

Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. Here, we investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy. Methods and results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation-negative relatives. A total of 38 (obligate) mutation-positive patients died suddenly or suffered life-threatening ventricular arrhythmia. Of these, 18 were aged >40 years, a high proportion of which had a clinical diagnosis of hypertension and/or cardiac hypertrophy. While pacemaker implantation was highly protective in preventing bradycardia-related SCD in young mutation-positive patients, seven of them aged >40 experienced life-threatening arrhythmic events despite pacemaker treatment. Of these, six had a diagnosis of hypertension/hypertrophy, pointing to a modulatory role of this co-morbidity. Induction of hypertrophy in adult mice carrying the homologous mutation (Scn5a1798insD/+) caused SCD and excessive conduction disturbances, confirming a modulatory effect of hypertrophy in the setting of the mutation. The deleterious effects of the interaction between hypertrophy and the mutation were prevented by genetically impairing the pro-hypertrophic response and by pharmacological inhibition of the enhanced late sodium current associated with the mutation. Conclusion: This study provides the first evidence for a modulatory effect of co-existing cardiac hypertrophy on arrhythmia risk and treatment efficacy in inherited sodium channelopathy. Our findings emphasize the need for continued assessment and rigorous treatment of this co-morbidity in SCN5A mutation-positive individuals.

Periodontal regeneration via chemoattractive constructs.

AIM: Chemoattractants, such as stromal cell-derived factor-1α (SDF-1α), can offer an advantage for periodontal regeneration by recruiting the patient's own stem cells to stimulate self-repair. We here developed a chemoattractive construct for periodontal regeneration using SDF-1α and evaluated its efficacy in vivo. MATERIALS AND METHODS: SDF-1α was loaded on gelatin sponge and tested in vitro for SDF-1α release. Subsequently, SDF-1α constructs were implanted into rat periodontal defects for 1 and 6 weeks, with unloaded materials and empty defects as controls. The regenerative efficacy was evaluated by micro-CT, histological and histomorphometrical analyses. RESULTS: In vitro results showed limited SDF-1α release up to 35 days. In contrast, SDF-1α constructs significantly improved periodontal defect regeneration in terms of alveolar bone height, new bone area and functional ligament length. Additionally, SDF-1α constructs decreased the inflammatory response at Week 6. CONCLUSION: Chemoattractive constructs significantly improved periodontal regeneration in terms of alveolar bone height, new bone area and functional ligament length.

Modifications of Poly(Methyl Methacrylate) Cement for Application in Orthopedic Surgery.

Even with the emerging of newly-developed bone substitutes, poly(methyl methacrylate) (PMMA) cement is still a widely-used bone replacing biomaterial in orthopedic surgery with a long history. However, aseptic loosening, infection of the prosthesis and thermal necrosis to surrounding tissue are the common complications of PMMA. Therefore, additives have been incorporated in PMMA cement to target those problems. This chapter summarizes different additives to improve the performance of the PMMA cement, i.e.: (1) bioceramic additives; (2) filler additives; (3) antibacterial additives; (4) porogens; (5) biological agents, and (6) mixed additives. To improve the biological and mechanical performance of PMMA cement, mixed additives aiming to fabricate multifunctional PMMA seem the most suitable choice. Although in vivo animal studies have been conducted, long-term and clinical studies are still needed to evaluate the modifications of multifunctional PMMA cement for matching a specific clinical application.

A comparative study of the bone contact to zirconium and titanium implants after 8 weeks of implantation in rabbit femoral condyles.

Zirconium (Zr) has been found to have comparable characteristics to titanium with a favorable modulus of elasticity. In addition, the release of Zr-ions of a Zr implant is supposed to further increase the bone-to-implant response. Therefore, the objective of this study is to compare the bone contact to Zr and Ti implants in the femoral trabecular bone of rabbits. In addition, implants provided with a hydroxyapatite (HA) coating were included, as such a coating was proven before to enhance the secondary implant stability. A total of 32 implants consisting of 16 Zr (8 HA coated) and 16 Ti (8 HA coated) implants were installed in the femoral condyle of 16 rabbits. After 8 weeks of healing the femoral condyles including the implants were retrieved and studied histologically. The bone-to-implant contact (BIC) percentage was assessed and analyzed statistically. The BIC values of the uncoated Zr and Ti implants showed comparable BIC values (45.1 ± 14.8 vs. 45.5 ± 13.1). The BIC percentage was slightly higher for HA coated Zr and Ti implants (60.3 ± 17.1, 59.8 ± 16.4, respectively) compared to uncoated, but statistical testing indicated that this difference was not significant. It can be concluded that Zr and Ti implants show a comparable bone-implant contact after 8 weeks of implantation in the currently used rabbit model. In addition, the deposition of a sputtered HA coating on both Zr and Ti implants did not further improve their bone integration.

Macrophage type modulates osteogenic differentiation of adipose tissue MSCs.

Since the reconstruction of large bone defects remains a challenge, knowledge about the biology of bone healing is desirable to develop novel strategies for improving the treatment of bone defects. In osteoimmunology, macrophages are the central component in the early stage of physiological response after bone injury and bone remodeling in the late stage. During this process, a switch of macrophage phenotype from pro-inflammatory (M1) to anti-inflammatory (M2) is observed. An appealing option for bone regeneration would be to exploit this regulatory role for the benefit of osteogenic differentiation of osteoprogenitor cells (e.g., mesenchymal stem cells; MSCs) and to eventually utilize this knowledge to improve the therapeutic outcome of bone regenerative treatment. In view of this, we focused on the in vitro interaction of different macrophage subtypes with adipose tissue MSCs to monitor the behavior (i.e. proliferation, differentiation and mineralization) of the latter in dedicated co-culture models. Our data show that co-culture of MSCs with M2 macrophages, but not with M1 macrophages or M0 macrophages, results in significantly increased MSC mineralization caused by soluble factors. Specifically, M2 macrophages promoted the proliferation and osteogenic differentiation of MSCs, while M0 and M1 macrophages solely stimulated the osteogenic differentiation of MSCs in the early and middle stages during co-culture. Secretion of the soluble factors oncostatin M (OSM) and bone morphogenetic protein 2 (BMP-2) by macrophages showed correlation with MSC gene expression levels for OSM-receptor and BMP-2, suggesting the involvement of both signaling pathways in the osteogenic differentiation of MSCs.

Next Generation Hemostatic Materials Based on NHS-Ester Functionalized Poly(2-oxazoline)s.

In order to prevent hemorrhage during surgical procedures, a wide range of hemostatic agents have been developed. However, their efficacy is variable; hemostatic devices that use bioactive components to accelerate coagulation are dependent on natural sources, which limits reproducibility. Hybrid devices in which chain-end reactive poly(ethylene glycol) is employed as active component sometimes suffer from irregular cross-linking and dissolution of the polar PEG when blood flow is substantial. Herein, we describe a synthetic, nonbioactive hemostatic product by coating N-hydroxysuccinimide ester (NHS)-functional poly(2-oxazoline)s (POx-NHS) onto gelatin patches, which acts by formation of covalent cross-links between polymer, host blood proteins, gelatin and tissue to seal the wound site and prevent hemorrhage during surgery. We studied different process parameters (including polymer, carrier, and coating technique) in direct comparison with clinical products (Hemopatch and Tachosil) to obtain deeper understanding of this class of hemostatic products. In this work, we successfully prove the hemostatic efficacy of POx-NHS as polymer powders and coated patches both in vitro and in vivo against Hemopatch and Tachosil, demonstrating that POx-NHS are excellent candidate polymers for the development of next generation hemostatic patches.

Comparison of different surface modifications for titanium implants installed into the goat iliac crest.

OBJECTIVES: This in vivo study with implants installed in the goat iliac crest was performed to determine whether the biological and mechanical properties of the bone-to-implant interface are influenced by (i) the type of implant anchorage (i.e., mono- vs. bicortical placement), and (ii) the presence of a bioactive hydroxyapatite (HA) or composite HA/bioactive glass (BG) coatings. MATERIALS AND METHODS: A total of 96 titanium (Ti) implants w/- coatings (Ti, Ti-HA & Ti-HABG; n = 8) were mono- or bicortically placed in the iliac crest of eight goats. At installation and after 4 weeks, implant stability was determined using insertion and removal torque testing (ITQ & RTQ). The peri-implant bone response was histologically and histomorphometrically evaluated by means of bone-to-implant contact (BIC%) and bone area (BA%). RESULTS: Monocortical implants demonstrated significantly lower RTQ values in comparison to ITQ values, whereas for bicortical implant placement RTQ and ITQ were similar. Further, mean RTQ values for monocortical implants were significantly lower in comparison to bicortical implants. Histomorphometrical evaluation demonstrated higher BIC% and BA% for bicortical implants compared to monocortical implants. For bicortical implants, BA% in the inner peri-implant region (0-500 µm) was significantly higher compared to the middle (500-1000 µm) and outer (1000-1500 µm) region. Also, a significant correlation was observed for monocortical implants between RTQ and BIC% and BA%. For surface modifications, no significant differences were found in ITQ and RTQ, for neither mono- nor bicortical implants. Histomorphometrically, HABG-coated implants demonstrated significantly higher BIC% compared to GAE surfaces for both mono- and bicortical implants. Bicortical HA-coated implants revealed significant higher BA% in the inner peri-implant region (0-500 µm) in comparison to bicortical GAE implants. CONCLUSIONS: This study demonstrated that bicortical implant placement beneficially affects implant stability during the early phase of osseointegration. A significant correlation between removal torque and bone-to-implant contact and bone area for monocortical implants was observed, but not for bicortical implants. Therefore, histomorphometrical data should be interpreted with caution to predict the biomechanical implant fixation of bone implants over time. Regarding surface modifications, in the present implantation model, the addition of BG to an RF magnetron sputtered HA coating enhanced the biological behavior of the coating compared to grit-blasted/acid-etched implants.

Nanometer-grooved topography stimulates trabecular bone regeneration around a concave implant in a rat femoral medulla model.

In the present study, a method was developed to reproduce two nanogrooved patterns (groove width/ridge width/depth: 150/150/50 nm and 200/800/70 nm) into cylindrical epoxy resin implants, which were subsequently coated with 20 nm of titanium. Also, implants with a conventional surface roughness (Rq=1.6 µm) were produced. After cytocompatibility analysis of the produced surfaces, implants were installed into the femoral condyle of rats for 4 and 8 weeks. The histomorphometrical analysis of bone volume in a 100 µm wide zone close to the implant surface showed that only for the 200/800 grooves the amount of bone increased significantly between 4 and 8 weeks of implantation. In addition, at the late time point only implants with the 200/800 pattern revealed a significantly higher bone volume compared to the rough controls. In conclusion, the 200/800 grooved pattern can positively influence bone volume adjacent to the implant surface, and should be evaluated and optimized in further (pre-)clinical studies.

Antibacterial effects of electrospun chitosan/poly(ethylene oxide) nanofibrous membranes loaded with chlorhexidine and silver.

To prevent percutaneous device associated infections (PDAIs), we prepared electrospun chitosan/poly(ethylene oxide) (PEO) nanofibrous membrane containing silver nanoparticles as an implantable delivery vehicle for the dual release of chlorhexidine and silver ions. We observed that the silver nanoparticles were distributed homogeneously throughout the fibers, and a fast release of chlorhexidine in 2days and a sustained release of silver ions for up to 28days. The antibacterial efficacy of the membranes against Staphylococcus aureus showed that the membranes exhibited an obvious inhibition zone upon loading with either chlorhexidine (20µg or more per membrane) or AgNO3 (1 and 5wt% to polymer). Furthermore, long-term antibacterial effect up to 4days was verified using membranes containing 5wt% AgNO3. The results suggest that the membranes have strong potential to act as an active antibacterial dressing for local delivery of antibacterial agents to prevent PDAIs.

Influence of polymeric additives on the cohesion and mechanical properties of calcium phosphate cements.

To expand the clinical applicability of calcium phosphate cements (CPCs) to load-bearing anatomical sites, the mechanical and setting properties of CPCs need to be improved. Specifically, organic additives need to be developed that can overcome the disintegration and brittleness of CPCs. Hence, we compared two conventional polymeric additives (i.e. carboxylmethylcellulose (CMC) and hyaluronan (HA)) with a novel organic additive that was designed to bind to calcium phosphate, i.e. hyaluronan-bisphosphonate (HABP). The unmodified cement used in this study consisted of a powder phase of α-tricalcium phosphate (α-TCP) and liquid phase of 4% NaH2PO4·2H2O, while the modified cements were fabricated by adding 0.75 or 1.5 wt% of the polymeric additive to the cement. The cohesion of α-TCP was improved considerably by the addition of CMC and HABP. None of the additives improved the compression and bending strength of the cements, but the addition of 0.75% HABP resulted into a significantly increased cement toughness as compared to the other experimental groups. The stimulatory effects of HABP on the cohesion and toughness of the cements is hypothesized to derive from the strong affinity between the polymer-grafted bisphosphonate ligands and the calcium ions in the cement matrix.

Influence of bone marrow-derived mesenchymal stem cells pre-implantation differentiation approach on periodontal regeneration in vivo.

AIM: The implantation of bone marrow-derived mesenchymal stem cells (MSCs) has previously been shown successful to achieve periodontal regeneration. However, the preferred pre-implantation differentiation strategy (e.g. maintenance of stemness, osteogenic or chondrogenic induction) to obtain optimal periodontal regeneration is still unknown. This in vivo study explored which differentiation approach is most suitable for periodontal regeneration. MATERIALS AND METHODS: Mesenchymal stem cells were obtained from Fischer rats and seeded onto poly(lactic-co-glycolic acid)/poly(ɛ-caprolactone) electrospun scaffolds, and then pre-cultured under different in vitro conditions: (i) retention of multilineage differentiation potential; (ii) osteogenic differentiation approach; and (iii) chondrogenic differentiation approach. Subsequently, the cell-scaffold constructs were implanted into experimental periodontal defects of Fischer rats, with empty scaffolds as controls. After 6 weeks of implantation, histomorphometrical analyses were applied to evaluate the regenerated periodontal tissues. RESULTS: The chondrogenic differentiation approach showed regeneration of alveolar bone and ligament tissues. The retention of multilineage differentiation potential supported only ligament regeneration, while the osteogenic differentiation approach boosted alveolar bone regeneration. CONCLUSION: Chondrogenic differentiation of MSCs before implantation is a useful strategy for regeneration of alveolar bone and periodontal ligament, in the currently used rat model.

Annual failure rates and marginal bone-level changes of immediate compared to conventional loading of dental implants. A systematic review of the literature and meta-analysis.

BACKGROUND: Immediate loading of dental implants appears to be a successful option. Questions still remain whether annual failure rates (AFRs) as well as annual marginal bone-level changes are comparable with conventionally loaded implants. HYPOTHESIS: Immediately loaded implants (≤24 h after implantation) do not show different annual survival rates or peri-implant bone-level changes as compared to conventionally loaded implants (≥3 months after implantation). MATERIAL AND METHODS: An electronic search in the National Library of Medicine and in Cochrane Central Register of Controlled Trials was performed for articles published up to November 2013. Only publications in English were considered. Additionally, the bibliographies of the full-text papers were searched. Primary outcome variable was percentage AFR; secondary outcome variable was annual radiographic bone-level change. RESULTS: Electronic search yielded 154 full-text articles; ten randomized controlled clinical trials were eventually meta-analyzed. Annual failure rates were 2.3% and 3.4% for conventionally and immediately loaded implants, respectively. No difference in implant failure rates was found (RR: 0.82). Regarding marginal bone-level changes, the weighted mean difference (WMD) between immediate and conventional loading amounted to 0.02 mm at 1 year (P > 0.05), to 0.08 mm at 2 years (P > 0.05), -0.10 mm at 3 years (P > 0.05) and -0.3 mm at 5 years (P < 0.05). The total WMD for the combined follow-up was 0.01 mm (P > 0.05). CONCLUSION: No clinically relevant differences regarding annual failure rates or radiographic bone-level changes between conventionally and immediately loaded implants can be found for up to 5 years of follow-up.

Comparative evaluation of the combined application of titanium implants and calcium phosphate bone substitutes in a rabbit model.

OBJECTIVES: To study the healing of defects around titanium implants filled with biphasic calcium phosphates (BCP). MATERIAL AND METHODS: Forty custom-made, titanium implants (Ti) with a diameter of 5 mm, and length of 8 mm, with two-sided gaps, were fabricated and installed in the femoral condyle of 20 rabbits. Following a randomization protocol, implants were alternately installed in one condyle without BCP bone substitute material (Ti) in the gaps and in the contralateral condyle gaps were filled with BCP bone substitute material (Ti+BCP). The implants were retrieved after 4 and 12 weeks of healing, after which histological and histomorphometrical analyses were done to assess the percentage of bone implant contact (BIC), the percentage of bone area (BA) and the percentage of particle area (PA) within the region of interest (ROI); the rectangular area joining the two arms of the L-shaped implant was considered as the ROI. RESULTS: After 4 and 12 weeks of healing, Ti+BCP showed significantly higher BIC and BA values compared to Ti. Further, the BCP particles showed a significant decrease from 4 to 12 weeks of healing. The BCP particles (PA) showed a significant reduction from 31.6 ± 11.0% at 4 weeks to 21.0 ± 7.2% at 12 weeks. CONCLUSION: The addition of BCP bone substitute to fill peri-implant gaps significantly enhanced both bone formation (~2.5-fold) and bone to implant contact (>2-fold) for the custom-made titanium implants with two-sided gaps.