Development and Characterization of Gadolinium and Copper Reinforced Bioactive Glass: An In Vitro Study.

INTRODUCTION: Bioactive glass, an innovative alloplastic material utilizing a matrix of silica particles combined with calcium and phosphorus, has been widely employed for the regeneration of bony defects due to its bone-forming capabilities and biocompatibility. Nevertheless, it comes with several drawbacks, including a slow degradation rate, low mechanical strength, and susceptibility to fractures. To address these issues, the present research was done to develop and characterize a novel bioactive glass incorporating gadolinium (Gd) and copper (Cu). METHODS: The bioactive glass doped with Gd and Cu were synthesized and subjected to characterization through X-ray diffraction (XRD), scanning electron microscopy (SEM), and attenuated total reflectance-infrared (ATR-IR) analysis. RESULTS: The bioactive glass, enriched with Gd and Cu, underwent analysis using ATR-IR spectroscopy, XRD, and SEM. ATR-IR revealed characteristic silicate bands, while SEM indicated the presence of particles larger than 4 µm. XRD analysis identified the formation of Na2Ca4(PO4)2SiO4 (Silicorhenatite), Na2Ca2Si3O9 (Combeite), and wollastonite (calcium inosilicate mineral; CaSiO3). The crystalline nature of these compounds contributed to the favorable mechanical properties of the bioactive glass. CONCLUSION: In summary, the creation of the innovative Gd-Cu-incorporated bioactive glass demonstrates favorable mechanical characteristics, suggesting significant promise for augmenting bone regeneration.

IGF2 promotes alveolar bone regeneration in murine periodontitis via inhibiting cGAS/STING-mediated M1 macrophage polarization.

Periodontitis is a chronic inflammatory disease with the destruction of supporting periodontal tissue. This study evaluated the role of insulin-like growth factor 2 (IGF2) in periodontitis by inhibiting the polarization of M1 macrophages via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. IGF2 was enriched in the gingival tissue of murine periodontitis model identified by RNA sequencing. IGF2 application alleviated the expression of pro-inflammatory factors and promoted osteogenesis and the expression of related genes and proteins in a dose-dependent manner in periodontitis. The result of micro-CT verified this finding. Both in vivo and in vitro results revealed that IGF2 decreased the polarization of M1 macrophages and pro-inflammatory factors by immunofluorescence staining, flow cytometry, western blotting and RT-PCR. IGF2 application promoted the osteogenic ability of periodontal ligament fibroblasts (PDLFs) indirectly via its inhibition of M1 polarization evaluated by alkaline phosphatase and alizarin red staining. Then, the cGAS/STING pathway was upregulated in periodontitis and macrophages challenged by LPS, the inhibition of which led to downregulation of M1 polarization. Furthermore, IGF2 could downregulate cGAS, STING and the phosphorylation of P65. Collectively, our study indicates IGF2 can regulate the polarization of M1 macrophages via the cGAS/STING pathway and highlights the promising future of IGF2 as a therapeutic treatment for periodontitis.

Antimicrobial peptides in bone regeneration: mechanism and potential.

INTRODUCTION: Antimicrobial peptides (AMPs) are small-molecule peptides with a unique antimicrobial mechanism. Other notable biological activities of AMPs, including anti-inflammatory, angiogenesis, and bone formation effects, have recently received widespread attention. These remarkable bioactivities, combined with the unique antimicrobial mechanism of action of AMPs, have led to their increasingly important role in bone regeneration. AREAS COVERED: In this review, on the one hand, we aimed to summarize information about the AMPs that are currently used for bone regeneration by reviewing published literature in the PubMed database. On the other hand, we also highlight some AMPs with potential roles in bone regeneration and their possible mechanisms of action. EXPERT OPINION: The translation of AMPs to the clinic still faces many problems, but their unique antimicrobial mechanisms and other conspicuous biological activities suggest great potential. An in-depth understanding of the structure and mechanism of action of AMPs will help us to subsequently combine AMPs with different carrier systems and perform structural modifications to reduce toxicity and achieve stable release, which may be a key strategy for facilitating the translation of AMPs to the clinic.

A Wood-Derived Periosteum for Spatiotemporal Drug Release: Boosting Bone Repair through Anisotropic Structure and Multiple Functions.

Existing artificial periostea face many challenges, including difficult-to-replicate anisotropy in mechanics and structure, poor tissue adhesion, and neglected synergistic angiogenesis and osteogenesis. Here, inspired by natural wood (NW), a wood-derived elastic artificial periosteum is developed to mimic the structure and functions of natural periosteum, which combines an elastic wood (EW) skeleton, a polydopamine (PDA) binder layer, and layer-by-layer (LBL) biofunctional layers. Specifically, EW derived from NW is utilized as the anisotropic skeleton of artificial periosteum to guide cell directional behaviors, moreover, it also shows a similar elastic modulus and flexibility to natural periosteum. To further enhance its synergistic angiogenesis and osteogenesis, surface LBL biofunctional layers are designed to serve as spatiotemporal release platforms to achieve sequential and long-term release of pamidronate disodium (PDS) and deferoxamine (DFO), which are pre-encapsulated in chitosan (CS) and hyaluronic acid (HA) solutions, respectively. Furthermore, the combined effect of PDA coating and LBL biofunctional layers enables the periosteum to tightly adhere to damaged bone tissue. More importantly, this novel artificial periosteum can boost angiogenesis and bone formation in vitro and in vivo. This study opens up a new path for biomimetic design of artificial periosteum, and provides a feasible clinical strategy for bone repair.

Osteogenic Potential of Magnesium Oxide Nanoparticles in Bone Regeneration: A Systematic Review.

Guided bone regeneration (GBR) plays a crucial role in the augmentation of alveolar bone, especially in cases of dental implants. The main principle behind using membranes in guided tissue regeneration (GTR) is to prevent epithelial downgrowth as well as connective tissue on the root surface. However, the membranes lack some major properties, such as osteogenic and antimicrobial properties. Magnesium (Mg) is one of the biodegradable materials that is gaining interest because of its favourable mechanical properties and biocompatibility. It also possesses pro-osteogenic properties and significant inhibition of biofilm formation and maturation. These features have attracted increasing interest in using magnesium oxide nanoparticles in GBR membrane applications. This systematic review assesses the osteogenic potential of magnesium oxide nanoparticles in periodontal bone regeneration. The literature search used PubMed, PubMed Central, Medline, and Cochrane databases to examine systematic reviews published till March 2023. Seven articles were included based on the selection criteria. We included all in vitro and in vivo clinical studies based on the osteogenic potential of magnesium oxide nanoparticles in periodontal bone regeneration. The seven studies provided evidence that magnesium oxide nanoparticles, when incorporated in any substrate, showed higher osteogenic potential in terms of higher alkaline phosphatase levels, bone volume fraction, and bone mineral density. The optimum concentration of magnesium oxide can be an ideal additive to various substrates to promote bone regeneration. Because most of the studies were conducted on calvarial defects, further studies should focus only on bone regeneration related to periodontal regeneration.

Cissus Extracts in Dentistry: A Comprehensive Review on its Untapped Potential.

Natural products have received a lot of attention in a variety of medical sectors, including dentistry. Cissus, a flowering plant genus, has long been used for its therapeutic benefits. The purpose of this review is to thoroughly investigate the possibilities of Cissus extracts in dentistry. To that end, we used specific selection criteria for the selection of pertinent scientific articles published in the scientific information databases of PubMed, Web of Science, Google Scholar, Scopus, and ProQuest. We found that the diverse array of bioactive compounds found in varied species of Cissus holds promise for applications ranging from oral wound healing to periodontal health. This review summarizes known studies on antibacterial, anti-inflammatory, and tissue-regenerative characteristics of Cissus extracts, shedding light on their potential significance in modernizing modern dental practices. It exerts that Cissus extracts have the potential to supplement established dentistry therapies by providing all-natural remedies for a variety of oral health conditions.

Evaluating the Role of Nanoparticles in Enhancing Bone Regeneration in Dental Implantology.

Background: Dental implantology has witnessed substantial progress in recent years, driven by a growing emphasis on optimizing bone regeneration around dental implants. Nanoparticles have emerged as a potential tool for enhancing osseointegration and bone tissue regeneration. Materials and Methods: This human clinical trial enrolled 60 adult participants requiring dental implants. Patients were randomly assigned to one of two groups: a control group receiving conventional dental implants, and an experimental group receiving dental implants with nanoparticle-coated surfaces. Radiographic imaging, histological analysis of bone biopsies, and implant stability assessments were conducted at three and six months post-implantation. Results: Histological examination of bone biopsies revealed a statistically significant increase in new bone formation in the experimental group compared to the control group at both three and six months (P < 0.05). Radiographic assessment demonstrated a 25% higher bone density around nanoparticle-coated implants (P < 0.01) at the six-month mark. Implant stability quotient (ISQ) measurements indicated a 20% greater stability in the experimental group (P < 0.05) at the same time point. Conclusion: This human clinical trial provides strong evidence that the incorporation of nanoparticles on dental implant surfaces enhances bone regeneration and osseointegration in a human population.

Update on the use of 45S5 bioactive glass in the treatment of bone defects in regenerative medicine.

Bone regeneration is a critical area in regenerative medicine, particularly in orthopedics, demanding effective biomedical materials for treating bone defects. 45S5 bioactive glass (45S5 BG) is a promising material because of its osteoconductive and bioactive properties. As research in this field continues to advance, keeping up-to-date on the latest and most successful applications of this material is imperative. To achieve this, we conducted a comprehensive search on PubMed/MEDLINE, focusing on English articles published in the last decade. Our search used the keywords "bioglass 45S5 AND bone defect" in combination. We found 27 articles, and after applying the inclusion criteria, we selected 15 studies for detailed examination. Most of these studies compared 45S5 BG with other cement or scaffold materials. These comparisons demonstrate that the addition of various composites enhances cellular biocompatibility, as evidenced by the cells and their osteogenic potential. Moreover, the use of 45S5 BG is enhanced by its antimicrobial properties, opening avenues for additional investigations and applications of this biomaterial.

How to explain the beneficial effects of platelet-rich plasma.

Platelet-rich plasma (PRP) is the platelet and leukocyte-containing plasmatic fraction of anticoagulated autologous blood. While evidence supporting the clinical use of PRP in dentistry is low, PRP is widely used in sports medicine, orthopedics, and dermatology. Its beneficial activity is commonly attributed to the growth factors released from platelets accumulating in PRP; however, evidence is indirect and not comprehensive. There is thus a demand to revisit PRP with respect to basic and translational science. This review is to (i) recapitulate protocols and tools to prepare PRP; (ii) to discuss the cellular and molecular composition of PRP with a focus on platelets, leukocytes, and the fibrin-rich extracellular matrix of coagulated plasma; and finally (iii) to discuss potential beneficial effects of PRP on a cellular and molecular level with an outlook on its current use in dentistry and other medical fields.

A new approach for vertical bone augmentation: Reconstructing bony peaks before GBR with a customized titanium mesh.

This image article presents a single patient receiving a reconstructed fibular bony peak (BP) for guided bone regeneration (GBR) with a customized titanium mesh. The patient was informed and understood the objectives and signed a written informed consent document before surgery.

Application of sticky bone combined with concentrated growth factor (CGF) for horizontal alveolar ridge augmentation of anterior teeth: a randomized controlled clinical study.

OBJECTIVE: This study was designed to estimate the effect of sticky bone combined with concentrated growth factor (CGF) on anterior alveolar horizontal augmentation during implantation. METHODS: Twenty-eight patients were randomly assigned to either the test group (Group 1, n = 14) or the control group (Group 2, n = 14). Patients in Group 1 and Group 2 underwent GBR using sticky bone combined with CGF and bone powders mixed with saline, respectively. On postoperative Day 7, the patients completed the visual analogue scale (VAS). Three-dimensional models of maxillary alveolar bone were reconstructed from CBCT data at different periods, and the bone volume conversion rate was calculated with the assistance of a measurement marker guide. Labial bone thickness before and after trauma closure and bone density at six months postoperatively were also measured. RESULTS: The mean bone volume conversion rate for Group 1 (72.09 ± 12.18%) was greater than that for Group 2 (57.47 ± 9.62%, P = 0.002). The VAS score was lower for Group 1 than for Group 2 (P = 0.032). At six months postoperatively, greater bone density was found in patients in Group 1 than in those in Group 2, although the difference was not statistically significant (P > 0.05). The change in the thickness of the labial bone graft material in Group 1 was smaller than that in Group 2 (P = 0.025). CONCLUSION: Sticky bone combined with CGF was able to achieve better bone augmentation than conventional GBR. With excellent mechanical properties and the capacity to release growth factors, sticky bone is an ideal material for bone grafting. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trial Registry on 10/04/2022 (Identification number: ChiCTR2200058500).

Horizontal ridge augmentation using guided bone regeneration with an association of particulate allografts mixed with platelet-rich fibrin, collagen membrane and tent-screws: A prospective study.

BACKGROUND: Guided Bone Regeneration (GBR) is a versatile technique employed not only to correct pre-implant alveolar bone defects but also to facilitate bone defect correction during simultaneous implant placement. The effectiveness of GBR varies significantly among different protocols, as reported in the literature. This study specifically aimed to radiologically evaluate the horizontal bone gain obtained using a GBR procedure combining a particulate allograft, platelet-rich fibrin, resorbable collagen membrane, and screw tents. MATERIALS AND METHODS: A total of 42 patients with an insufficient alveolar bone width for dental implant placement were treated with a GBR technique using a mixture of particulate allograft (demineralised freeze-dried bone allograft 300-500 and 500-1000 µm), advanced platelet-rich fibrin (A-PRF), resorbable collagen membranes and screws tents (1.2 mm in diameter). Over the course of the study, a total of 63 GBR procedures were performed on these patients. Bone gains were measured by cone-beam computed tomography at 9.1 ± 2.0 months post-operative. RESULTS: A significant mean increase (P < 0.001) of 3.2 ± 0.9 mm at the sites of the greatest bone defect was observed. This improvement was consistent across various locations, including both maxillary and mandibular regions, and in cases of terminal and embedded edentulism, without any post-operative complications during the entire post-operative follow-up. All patients benefited from implant placement following the bone augmentation protocol. CONCLUSION: GBR combining particulate allografts, A-PRF, collagen membranes, and screw tents achieves reliable, predictable, and reproducible clinical gains that allow for future implant placement.

Fabrication of Bioresorbable Barrier Membranes from Gelatin/Poly(4-Hydroxybutyrate) (P4HB).

Dental implant surgery is a procedure that replaces damaged or missing teeth with an artificial implant. During this procedure, guided bone regeneration (GBR) membranes are commonly used to inhibit the migration of epithelium and GBR at the surgical sites. Due to its biodegradability, good biocompatibility, and unique biological properties, gelatin (GT) is considered a suitable candidate for guiding periodontal tissue regeneration. However, GT-based membranes come with limitations, such as poor mechanical strength and mismatched degradation rates. To confront this challenge, a series of GT/poly(4-hydroxybutyrate) (P4HB) composite membranes are fabricated through electrospinning technology. The morphology, composition, wetting properties, mechanical properties, biocompatibility, and in vivo biodegradability of the as-prepared composite membranes are carefully characterized. The results demonstrate that all the membranes present excellent biocompatibility. Moreover, the in vivo degradation rate of the membranes can be manipulated by changing the ratio of GT and P4HB. The results indicate that the optimized GT/P4HB membranes with a high P4HB content (75%) may be suitable for periodontal tissue engineering because of their good mechanical properties and biodegradation rate compatible with tissue growth.

Favorable osteogenic activity of vericiguat doped in ß-tricalcium phosphate: In vitro and in vivo studies.

Recently, more and more studies have shown that guanylate cyclase, an enzyme that synthesizes cyclic guanosine monophosphate (cGMP), plays an important role in bone metabolism. Vericiguat (VIT), a novel oral soluble guanylate cyclase stimulator, directly generates cyclic guanosine monophosphate and reduce the death incidence from cardio-vascular causes or hospitalization. Recent studies have shown beneficial effects of VIT in animal models of osteoporosis, but very little is currently known about the effects of VIT on bone defects in the osteoporotic states. Therefore, in this study, ß-tricalcium phosphate (ß-TCP) was used as a carrier to explore the effect of local VIT administration on the repair of femoral metaphyseal bone defects in ovariectomized (OVX) rats. When MC3T3-E1 was cultured in the presence of H2H2, VIT, similar to Melatonin (MT), therapy could increase the matrix mineralization and ALP, SOD2, SIRT1, and OPG expression, reduce ROS and Mito SOX production, RANKL expression, Promote the recovery of mitochondrial membrane potential. In the OVX rat model, VIT increases the osteogenic effect of ß-TCP and better results were obtained at a dose of 5 mg. Local use of VIT can inhibit increased OC, BMP2 and RUNX2 expressions in bone tissue, while decreased SOST and TRAP expressions by RT-PCR and immunohistochemistry. Thereby, VIT stimulates bone regeneration and is a promising candidate for promoting bone repair in osteoporosis.

Fueling recovery: The importance of energy coupling between angiogenesis and osteogenesis during fracture healing.

Approximately half of bone fractures that do not heal properly (non-union) can be accounted to insufficient angiogenesis. The processes of angiogenesis and osteogenesis are spatiotemporally regulated in the complex process of fracture healing that requires a substantial amount of energy. It is thought that a metabolic coupling between angiogenesis and osteogenesis is essential for successful healing. However, how this coupling is achieved remains to be largely elucidated. Here, we will discuss the most recent evidence from literature pointing towards a metabolic coupling between angiogenesis and osteogenesis. We will describe the metabolic profiles of the cell types involved during fracture healing as well as secreted products in the bone microenvironment (such as lactate and nitric oxide) as possible key players in this metabolic crosstalk.

Biomaterial design for regenerating aged bone: materiobiological advances and paradigmatic shifts.

China's aging demographic poses a challenge for treating prevalent bone diseases impacting life quality. As bone regeneration capacity diminishes with age due to cellular dysfunction and inflammation, advanced biomaterials-based approaches offer hope for aged bone regeneration. This review synthesizes materiobiology principles, focusing on biomaterials that target specific biological functions to restore tissue integrity. It covers strategies for stem cell manipulation, regulation of the inflammatory microenvironment, blood vessel regeneration, intervention in bone anabolism and catabolism, and nerve regulation. The review also explores molecular and cellular mechanisms underlying aged bone regeneration and proposes a database-driven design process for future biomaterial development. These insights may also guide therapies for other age-related conditions, contributing to the pursuit of 'healthy aging'.

3D printed ß-tricalcium phosphate versus synthetic bone mineral scaffolds: A comparative in vitro study of biocompatibility.

BACKGROUND: ß-tricalcium phosphate (ß-TCP) has been successfully utilized as a 3D printed ceramic scaffold in the repair of non-healing bone defects; however, it requires the addition of growth factors to augment its regenerative capacity. Synthetic bone mineral (SBM) is a novel and extrudable carbonate hydroxyapatite with ionic substitutions known to facilitate bone healing. However, its efficacy as a 3D printed scaffold for hard tissue defect repair has not been explored. OBJECTIVE: To evaluate the biocompatibility and cell viability of human osteoprecursor (hOP) cells seeded on 3D printed SBM scaffolds via in vitro analysis. METHODS: SBM and ß-TCP scaffolds were fabricated via 3D printing and sintered at various temperatures. Scaffolds were then subject to qualitative cytotoxicity testing and cell proliferation experiments utilizing (hOP) cells. RESULTS: SBM scaffolds sintered at lower temperatures (600 °C and 700 °C) induced greater levels of acute cellular stress. At higher sintering temperatures (1100 °C), SBM scaffolds showed inferior cellular viability relative to ß-TCP scaffolds sintered to the same temperature (1100 °C). However, qualitative analysis suggested that ß-TCP presented no evidence of morphological change, while SBM 1100 °C showed few instances of acute cellular stress. CONCLUSION: Results demonstrate SBM may be a promising alternative to ß-TCP for potential applications in bone tissue engineering.

Multifunctional tannic acid-based nanocomposite methacrylated silk fibroin hydrogel with the ability to scavenge reactive oxygen species and reduce inflammation for bone regeneration.

The microenvironment of bone defect site is vital for bone regeneration. Severe bone defect is often accompanied with severe inflammation and elevated generation of reactive oxygen species (ROS) during bone repair. In recent years, the unfriendly local microenvironment has been paid more and more attention. Some bioactive materials with the ability to regulate the microenvironment to promote bone regeneration urgently need to be developed. Here, we develop a multifunctional composite hydrogel composed of photo-responsive methacrylate silk fibroin (SFMA), laponite (LAP) nanocomposite and tannic acid (TA), aiming to endow hydrogel with antioxidant, anti-inflammatory and osteogenic induction ability. Characterization results confirmed that the SFMA-LAP@TA hydrogel could significantly improve the mechanical properties of hydrogel. The ROS-Scavenging ability of the hydrogel enabled bone marrow mesenchymal stem cells (BMSCs) to survive against H2O2-induced oxidative stress. In addition, the SFMA-LAP@TA hydrogel effectively decreased the expression of pro-inflammatory factors in RAW264.7. More importantly, the SFMA-LAP@TA hydrogel could enhance the expression of osteogenic markers of BMSCs under inflammatory condition and greatly promote new bone formation in a critical-sized cranial defect model. Above all, the multifunctional hydrogel could effectively promote bone regeneration in vitro and in vivo by scavenging ROS and reducing inflammation, providing a prospective strategy for bone regeneration.

Zinc- and Fluoride-Releasing Bioactive Glass as a Novel Bone Substitute.

Bioglass 45S5, a silica-based glass, has pioneered a new field of biomaterials. Bioglass 45S5 promotes mineralization through calcium ion release and is widely used in the dental field, including toothpaste formulations. However, the use of Bioglass 45S5 for bone grafting is limited owing to the induction of inflammation, as well as reduced degradation and ion release. Phosphate-based glasses exhibit higher solubility and ion release than silica-based glass. Given that these glasses can be synthesized at low temperatures (approximately 1,000°C), they can easily be doped with various metal oxides to confer therapeutic properties. Herein, we fabricated zinc- and fluoride-doped phosphate-based glass (multicomponent phosphate [MP] bioactive glass) and further doped aluminum oxide into the MP glass (4% Al-MP glass) to overcome the striking solubility of phosphate-based glass. Increased amounts of zinc and fluoride ions were detected in water containing the MP glass. Doping of aluminum oxide into the MP glass suppressed the striking dissolution in water, with 4% Al-MP glass exhibiting the highest stability in water. Compared with Bioglass 45S5, 4% Al-MP glass in water had a notably reduced particle size, supporting the abundant ion release of 4% Al-MP glass. Compared with Bioglass 45S5, 4% Al-MP glass enhanced the osteogenesis of mouse bone marrow-derived mesenchymal stem cells. Mouse macrophages cultured with 4% Al-MP glass displayed enhanced induction of anti-inflammatory M2 macrophages and reduced proinflammatory M1 macrophages, indicating M2 polarization. Upon implanting 4% Al-MP glass or Bioglass 45S5 in a mouse calvarial defect, 4% Al-MP glass promoted significant bone regeneration when compared with Bioglass 45S5. Hence, we successfully fabricated zinc- and fluoride-releasing bioactive glasses with improved osteogenic and anti-inflammatory properties, which could serve as a promising biomaterial for bone regeneration.

Sclerotic bone: a sign of bone reaction in patients with medication related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction associated with antiresorptive drugs such as bisphosphonates and denosumab. When dealing with advanced and/or multiple MRONJ lesions undergoing surgical therapy, the extent of surgery is often a topic of discussion. The aim of this study was to identify the differences in bone density in and around the MRONJ lesion before and after surgical treatment to evaluate the needed surgical extend of the modelling osteotomy. In this retrospective study 26 patients with MRONJ lesions that were surgically treated in our department were observed. Length, width and bone density were measured in panoramic radiograph pre and postoperatively with the Imaging processing software Sidexis and ImageJ (Fiji). The necrotic area, the surrounding sclerotic area as well as the healthy contralateral side were observed. Measurements were performed by two independent observers. Pearson correlation was calculated to determine the interobserver variability. Bone density was significantly reduced in the necrotic bone area compared to the healthy unaffected contralateral reference side. The sclerotic bone area surrounding the necrosis showed increased bone density compared to the contralateral unaffected reference side. The density of the sclerotic bone area was increased in the previously affected MRONJ area in the postoperative panoramic radiograph. The pre and postoperative density showed no significant correlation to healing behaviour. The focus of the modelling osteotomy in surgical treatment of mature MRONJ lesions should be predominantly on the parts that appear necrotic and less dense in the panoramic radiograph as sclerotic areas might be an expression of bone reaction.