Biomedical subjects

Vittoria Perrotti

Publications and source records attributed to Vittoria Perrotti.

At least 19 recordsLinked to original sources

PubMed2006

Maxillary sinus augmentation with different biomaterials: a comparative histologic and histomorphometric study in man.

OBJECTIVE: Rehabilitation of the edentulous posterior maxilla with dental implants can be difficult because of insufficient bone volume caused by pneumatization of the maxillary sinus and crestal bone resorption. Different biomaterials have been used for sinus augmentation. The aim of the study was to compare different materials in maxillary sinus augmentation in man. METHODS: A total of 94 patients participated in this study. Inclusion criteria were maxillary partial (unilateral or bilateral) edentulism involving the premolar/molar areas, and the presence of 3-5-mm crestal bone between the sinus floor and alveolar ridge. A total of 362 implants were inserted. There were 9 biomaterials used in the sinus augmentation procedures. Each patient underwent 1 biopsy after 6 months. A total of 144 specimens were retrieved. RESULTS: None of the 94 patients had complications. All implants were stable, and x-ray examination showed dense bone around the implants. Mean follow-up was 4 years. There were 7 implants that failed. Histologic resultsshowed that almost all the particles of the different biomaterials (i.e., autologous bone, demineralized freeze-dried bone allograft Biocoral [Inoteb, St. Gonnery, France], Bioglass [US Biomaterials, Alachua, FL], Fisiograft [Ghimas, Bologna, Italy], PepGen P-15 [Dentsply Friadent CeraMed, Lakewood, CO], calcium sulfate, Bio-Oss [Geistlich Pharma AG, Wohlhusen, Switzerland], and hydroxyapatite) were surrounded by bone. Some biomaterials were more resorbable than others. Included are the histomorphometry clarified features of the newly formed bone around the different grafted particles. CONCLUSION: All biomaterials examined resulted in being biocompatible and seemed to improve new bone formation in maxillary sinus lift. No signs of inflammation were present. The data are very encouraging because of the high number of successfully treated patients and the good quality of bone found in the retrieved specimens.

Aged↗

PubMed2006

Histologic evaluation of 3 retrieved immediately loaded implants after a 4-month period.

OBJECTIVE: To perform a histologic and histomorphometric analysis of the peri-implant tissue reactions and bone-titanium interface in 3 immediately loaded (provisional loaded) titanium implants retrieved from a man after a loading period of 4 months. MATERIALS & METHODS: A 35-year-old patient with a maxillary partial edentulism did not want to wear a provisional removable prosthesis during the healing period. It was decided to insert 3 definitive implants and use 3 provisional implants for the transitional period. The provisional implants were loaded the same day with a resin prosthesis in occlusal contact. During the second surgical phase, after 4 months, the provisional prosthesis was removed, and the provisional implants were retrieved with a trephine bur. Before retrieval, all implants appeared to be clinically osseointegrated. The specimens were processed for observation under light microscopy. RESULTS: At low magnification, it was possible to observe that bone trabeculae were present around the implant. Areas of bone remodeling and haversian systems were present near the implant surface. Under polarized-light microscopy, it was possible to observe that in the coronal aspect of the thread, the lamellar bone showed lamellae that tended to run parallel to the implant surface, while in the inferior aspect of the thread, the bone lamellae ran perpendicular to the implant surface. CONCLUSIONS: Histologic data pertaining to these 3 immediately loaded implants, and retrieved after a 4-month loading period, show that immediate loading did not produce untoward effects on peri-implant bone healing.

Adult↗

PubMed2006

Genetic effects of Medpor on osteoblast-like cells.

Porous polyethylene (PP or Medpor) is an alloplastic material used worldwide for craniofacial reconstruction. Although several clinical studies are available, there is a lack as regard the genetic effects. Because PP is always fixed on bone and the mechanism by which PP acts on osteoblasts is unknown, we therefore attempted to address this question by using microarray techniques to identify genes that are differently regulated in osteoblasts exposed to PP. By using DNA microarrays containing 19,200 genes, we identified in osteoblast-like cell lines (i.e. MG-63) cultured on PP several genes where expression was differentially regulated. The differentially expressed genes cover a broad range of functional activities: 1) signal transduction, 2) transcription, 3) translation, 4) cell cycle regulation, 5) vesicular transport, and 6) production of cytoskeletal elements, cell-adhesion molecules and extracellular matrix components. The data reported are, to our knowledge, the first genetic portrait of osteoblast-like cells cultured on PP. They are relevant to better understanding of the molecular mechanism of bone-PP interaction and as a model for comparing other materials used for bone reconstruction.

Bone Substitutes↗

PubMed2006

Soft tissue myxoma: report of an unusual case located on the gingiva.

BACKGROUND: Soft tissue myxoma of the oral cavity is rare. Only three cases of myxoma of gingiva have been reported in the literature. We present a case of soft tissue myxoma arising from the left maxillary adherent gingiva in a 42-year-old male [correction of female] patient. METHODS: Histological examination showed spindle-shaped cells in a myxoid stroma. Immunohistochemical stains with S-100 protein were negative, while those with vimentin were positive. RESULTS: Clinical examination revealed a soft tissue mass, with tense elastic consistency on palpation. The overlying mucosa was normal and healthy. A clinical diagnosis of fibroma was given. Histological examination showed spindle-shaped and stellate cells, arranged in a myxoid fibrous stroma, with collagen fibres distributed uniformly. Scattered islands or strands of inactive odontogenic epithelium were present. On the basis of the histological and immunohistochemical findings, the final diagnosis was soft tissue myxoma. CONCLUSIONS: Further studies are necessary to clarify the origin and histogenesis of this lesion.

Adult↗

PubMed2006

Immediately loaded titanium implants with a porous anodized surface with at least 36 months of follow-up.

BACKGROUND: Results from some studies clearly suggest that immediate loading can achieve equal success rates as those found in delayed or unloaded implants. There is still a lack of knowledge about the role of surface oxide properties during the peri-implant bone healing processes. PURPOSE: The aim of this study was a clinical follow-up study of immediately loaded implants with a porous anodized surface. MATERIALS AND METHODS: A total of 142 TiUnite (Nobel Biocare, Göteborg, Sweden) implants were inserted from January to September 2001. All implants have been used in fixed restorations. Fifty implants were inserted in completely edentulous mandibles, and 69 implants were inserted in completely edentulous maxillae. All 119 implants were subjected to immediate functional loading (IFL) (immediate restoration with full occlusal contact). The other 23 implants, inserted in 12 patients, underwent immediate nonfunctional loading (INFL) (immediate restoration without occlusal contact) in different anatomical configurations (single tooth, small bridges in the anterior mandible, anterior maxilla, and posterior maxilla). All 142 implants have been followed for at least 3 years. RESULTS: All implants appeared to be osseointegrated from a clinical and radiographic point of view. No failures were observed in the IFL and INFL groups. The implant success was 100%. The mean marginal bone loss was 0.8 and 1.0 mm at 12 and 36 months, respectively. CONCLUSION: Implants with a porous anodized surface appear to work well under an immediate loading state in the long term.

Adult↗

PubMed2006

Screw vs cement-implant-retained restorations: an experimental study in the beagle. Part 2. Immunohistochemical evaluation of the peri-implant tissues.

Crestal bone loss has been reported to occur around dental implants. Even if the causes of this bone loss are not completely understood, the presence of a microgap between implant and abutment with a possible contamination of the internal portion of the implants has been suggested. The aim of this study was to see if there were differences in the vascular endothelial growth factor (VEGF) expression, microvessel density (MVD), proliferative activity (MIB-1), and inflammatory infiltrate in the soft tissues around implants with screwed and cemented abutments. Sandblasted and acid-etched implants were inserted in the mandibles of 6 Beagle dogs. Ten 3.5- x 10-mm root-form implants were inserted in each mandible. A total of 60 implants (30 with screwed abutments and 30 with cemented abutments) were used. After 12 months, all the bridges were removed and all abutments were checked for mobility. A total of 8 loosened screws (27%) were found in the screwed abutments, whereas no loosening was observed in cemented abutments. A gingival biopsy was performed in 8 implants with cemented abutments, in 8 implants with screwed abutments, and in 8 implants with unscrewed abutments. No statistically significant differences were found in the inflammatory infiltrate and in the MIB-1 among the different groups. No statistically significant difference was found in the MVD between screwed and cemented abutments (P = .2111), whereas there was a statistically significant difference in MVD between screwed and unscrewed abutments (P = .0277) and between cemented and unscrewed abutments (P = .0431). A low intensity of VEGF was prevalent in screwed and in cemented abutments, whereas a high intensity of VEGF was prevalent in unscrewed abutments. These facts could be explained by the effects induced, in the abutments that underwent a screw loosening, by the presence of bacteria inside the hollow portion of the implants or by enhanced reparative processes.

Acid Etching, Dental↗

PubMed2006

Immediately loaded blade implant retrieved from a after a 20-year loading period: a histologic and histomorphometric case report.

Immediate loading of root-form dental implants has shown promising results and offers treatment cost and convenience advantages to patients. Although blade implants have been immediately loaded for over 2 decades, the ability of this implant design to achieve osseointegration has been debated. The aim of the present study was to histologically evaluate the peri-implant tissues of an immediately loaded blade implant retrieved for abutment fracture after a 20-year loading period. Histologic samples were prepared and examined by light microscope. Compact, cortical, mature bone with well-formed osteons was present at the interface of the implant. Bone-to-implant contact was 51% +/- 6%. The histologic data showed that osseointegration was obtained in an immediately loaded blade implant inserted into the mandible, and that mineralized tissues were maintained at the interface over a long period (20 years).

Blade Implantation↗

PubMed2006

Maxillary sinus augmentation using an engineered porous hydroxyapatite: a clinical, histological, and transmission electron microscopy study in man.

Porous hydroxyapatite (HA) is a calcium-phosphate-based material that is biocompatible, nonimmunological, and osteoconductive, and has a macroporosity of about 200 to 800 microm. The pores seem to be able to induce migration, adhesion, and proliferation of osteoblasts inside the pore network and to promote angiogenesis inside the pore system. The aim of this study was to evaluate the clinical behavior and the histological and ultrastructural aspects of porous HA in maxillary sinus augmentation procedures. Twenty-four patients (19 men, 5 women; average age 53.4 years) in good general physical and mental health and with partially or completely edentulous maxillae were selected for this study. Six months after sinus floor elevation, at the time of dental implant placement, biopsies were carried out under local anesthesia. These bone cores were cut in half and were processed for light and transmission electron microscopy. After a mean 3 years after implantation, all implants are clinically in function and no surgical or prosthetic complications have occurred. Under light microscopy, newly formed bone was 38.5% +/- 4.5%, whereas the residual biomaterial represented 12% +/- 2.3% and the marrow spaces represented 44.6% +/- 4.2%. In addition, in the majority of cases, the biomaterial particles were in close contact with the bone, which appeared compact with the characteristic features of well-organized lamellar bone. A cement-like line was slightly visible at the bone-biomaterial interface, but there were no gaps or interposed connective tissue in between. A high quantity (about 40%) of newly formed bone was present. Bone was closely apposed to the biomaterials particles as shown in light microscopy and transmission electron microscopy. Moreover, no signs of inflammatory cell infiltrate or foreign body reaction were present. Also, most of the biomaterial was resorbed and only a small quantity (a little more than 10%) was still present. The results of our study show that porous HA can be a suitable synthetic material for bone regeneration in maxillary sinus augmentation procedures.

Absorbable Implants↗

PubMed2006

Bone contact around osseointegrated implants: a histologic study of acid-etched and machined surfaces.

Current literature reports that surface acid etching can improve bone--implant contact (BIC). The aim of this study was to evaluate the differences of BIC between acid-etched (Osseotite) and machined surface implants. Six white New Zealand mature rabbits were used in the present investigation. Each rabbit received two implants, specially made with two surfaces on it (one acid-etched and one machined) into each tibia. A total of 24 implants were inserted. Two animals each were killed at 15, 30, and 60 days after implant placement. Histomorphometry of BIC was statistically evaluated. The acid-etched surfaces showed a greater bone contact percentage than the machined ones during the early phase of healing (15 days), which was not statistically significant. On the other hand, after 30 and 60 days, the differences of BIC between acid-etched and machined surfaces were statistically significant. The acid-etched surface appears to improve BIC at a later stage of healing.

Acids↗

PubMed2006

Inflammatory infiltrate, microvessel density, nitric oxide synthase expression, vascular endothelial growth factor expression, and proliferative activity in peri-implant soft tissues around titanium and zirconium oxide healing caps.

BACKGROUND: The aim of the present study in humans was to conduct a comparative immunohistochemical evaluation of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) expression, inflammatory infiltrate, proliferative activity expression, and microvessel density (MVD) in peri-implant soft tissues of titanium and zirconium oxide healing caps. METHODS: Five patients, three men and two women (aged 30 to 66 years; mean: 49 years), participated in this study. All patients received dental implants that were 3.8 mm in diameter and 11 mm in length. All implants were left to heal in a non-submerged (single-stage) mode. Healing caps (3.8 mm in diameter and 3.0 mm in height) were inserted in all implants. Half of the implants were supplied with standard, prefabricated caps of commercially pure titanium, whereas the other half were provided with test zirconium oxide caps. After a 6-month healing period, a gingival biopsy was performed with a circular scalpel (5.5 mm in diameter) around the healing caps of both groups, without unscrewing or removing the healing caps. The dimensions of the gingival biopsies were 1.7 mm (5.5-3.8 mm) in thickness and 3 mm in height. RESULTS: Statistically significant differences were found in the microvessel density between titanium and zirconium oxide healing caps and group II (P < or = 0.0001). Statistically significant differences were likewise found in the low and high intensities of NOS1, NOS3, and VEGF (P < or = 0.0001). In conclusion, the high intensity of NOS1, NOS3, and VEGF were mostly expressed in the titanium group, whereas the low intensity of NOS1, NOS3, and VEGF were mostly expressed in the zirconium oxide group. CONCLUSIONS: In our specimens, the inflammatory infiltrate was mostly present in the titanium specimens. Their extension was much larger than that of the zirconium oxide specimens. Higher values of MVD were observed in the titanium specimens (29.1 versus 15.8). In addition, a higher expression of VEGF intensity was observed in the peri-implant tissues of titanium healing caps, whereas predominantly lower expressions of VEGF intensity were noted around the zirconium oxide healing caps. The Ki-67 expression was higher in the titanium specimens. All these data revealed that the tissues around titanium healing caps underwent a higher rate of inflammation-associated processes, most probably correlated to the higher inflammation processes observed in these tissues. A higher intensity expression of NOS1 and NOS3 was recorded in the tissues around titanium, whereas, on the contrary, a lower intensity of expression was found in the tissues around zirconium oxide specimens. These latter data indicate that the higher expression of these two mediators could be correlated to the higher amount of bacteria present around the titanium samples.

Adult↗

PubMed2005

Genetic effects of anorganic bovine bone (Bio-Oss) on osteoblast-like MG63 cells.

Bio-Oss (Geistlich, Wolhusen, Switzerland) is composed by anorganic bovine bone and is widely used in several bone regeneration procedures in oral surgery. How this biomaterial alters osteoblast gene expression to promote bone formation is poorly understood. We therefore attempted to address this question by using microarray techniques to identify genes that are differentially regulated in osteoblasts exposed to Bio-Oss. By using DNA microarrays containing 20,000 genes, we identified in osteoblast-like cells line (MG-63) cultured with Bio-Oss several genes which expression was significantly up- and down-regulated. The differentially expressed genes cover a broad range of functional activities: (a) signaling transduction, (b) transcription, (c) cell cycle regulation, (d) vesicular transport, (e) apoptosis, and (f) immunity. These results could explain the reported bioaffinity of Bio-Oss to host animals, its biological affinity to osteogenic cells and its capability to stimulate osteoblastic differentiation. The data reported are, to our knowledge, the first genetic portrait of Bio-Oss effects. They can be relevant to our improved understanding of the molecular mechanism underlying bone regenerative procedures and as a model for comparing other materials with similar clinical effects.

Animals↗

PubMed2005

Spindle cell lipoma of the floor of the mouth: report of a case.

Spindle cell lipoma is a benign tumour composed by: (1) mature fat cells; (2) spindle cells; (3) a myxoid matrix separated by thick bands of birefringent collagen. Only 14 cases have been reported in the oral cavity. The authors present the second case located in the floor of the mouth. The treatment of the lesion consists of a local excision.

Humans↗

PubMed2005

Effect of Vitamin C on pre-osteoblast gene expression.

Ascorbic acid (AA), also known as Vitamin C, is a cofactor required for the function of several hydroxylases. It is not synthesised in humans and has to be provided by diet. Its absence is responsible for scurvy, a condition related to the defective synthesis of collagen by the reduced function of prolylhydroxylase. AA is also a risk factor for periodontal disease. Recently, it has been shown that AA induces embryonic stem cells to differentiate into osteoblasts. The mechanism by which AA sustains pre-osteoblast proliferation and commitment is mediated through the synthesis of collagen type I, interaction with alpha2- and beta1-integrin, activation of the mitogen-activated protein kinase pathway, and phosphorylation of osteoblast-specific transcription factors. However, the multifunctional role of AA is not fully elucidated. MC3T3-E1 mouse calvaria-derived cell line is a well-defined in vitro model of pre-osteoblast differentiation, and AA is essential for the proliferation and differentiation of MC3T3-E1. By using DNA micro-arrays containing 15,000 genes, we identified several genes in MC3T3-E1 cultured with AA for 24h whose expression was significantly up or downregulated. The differentially expressed genes covered a broad range of functional activities: (1) cell growth; (2) metabolism; (3) morphogenesis; (4) cell death; (5) cell communication. The data reported are, to our knowledge, the first genetic portrait of early stage stimulation of pre-osteoblasts by AA, and may be relevant to better understand the molecular mechanism of pre-osteoblast proliferation and commitment. Elucidation of the molecular mechanism has important clinical implications because it may facilitate the correct use of AA to accelerate bone regeneration.

3T3 Cells↗

PubMed2005

Maxillary sinus augmentation with Bio-Oss particles: a light, scanning, and transmission electron microscopy study in man.

Biological interactions occurring at the bone-biomaterial interface are critical for long-term clinical success. Bio-Oss is a deproteinized, sterilized bovine bone that has been extensively used in bone regeneration procedures. The aim of the present study was a comparative light, scanning, and electron microscopy evaluation of the interface between Bio-Oss and bone in specimens retrieved after sinus augmentation procedures. Under light microscopy, most of the particles were surrounded by newly formed bone, while in a few cases, at the interface of some particles it was possible to observe marrow spaces and biological fluids. Under scanning electron microscopy, in most cases, the particle perimeter appeared lined by bone that was tightly adherent to the biomaterial surface. Transmission electron microscopy showed that the bone tissue around the biomaterial showed all the phases of the bone healing process. In some areas, randomly organized collagen fibers were present, while in other areas, newly formed compact bone was present. In the first bone lamella collagen fibers contacting the Bio-Oss surface were oriented at 243.73 +/- 7.12 degrees (mean +/- SD), while in the rest of the lamella they were oriented at 288.05 +/- 4.86 degrees (mean +/- SD) with a statistically significant difference of 44.32 degrees (p < 0.001). In the same areas the intensity of gray value was 172.56 +/- 18.15 (mean +/- SD) near the biomaterial surface and 158.71 +/- 21.95 (mean +/- SD) in the other part of the lamella with an unstatistically significant difference of 13.79 (p = 0.071). At the bone-biomaterial interface there was also an electron-dense layer similar to cement lines. This layer had a variable morphology being, in some areas, a thin line, and in other areas, a thick irregular band. The analyses showed that Bio-Oss particles do not interfere with the normal osseous healing process after sinus lift procedures and promote new bone formation. In conclusion, this study serves as a better understanding of the morphologic characteristics of Bio-Oss and its interaction with the surrounding tissues.

Absorbable Implants↗

PubMed2005

An in vitro model for dissecting distraction osteogenesis.

Distraction osteogenesis (DO) is a mechanotransduction process capable of generating viable osseous tissue by the gradual separation of osteotomized bone edges. Several variables are implicated in DO: magnitude of mechanical strain, distraction rate, and type of distracted bone. The combination of these factors acts on different types of cells inducing apoptosis, cell proliferation, and differentiation. The elucidation of the molecular mechanisms has important clinical implications because it may facilitate the use of recombinant proteins or gene therapy to accelerate bone regeneration. Previous reports have analyzed several molecules such as extracellular matrix proteins, cytokines, bone morphogenetic proteins, hormones, and angiogenic factors. Moreover, a single protein can have multifunctional roles. With such a huge number of mechanical, histologic, cellular, and molecular variables, there is the need to have a cell culture model that enables the selection of the effect of a specific strength to a single cell type at different time points and with or without cytokines. The analysis of the genetic profiling of a cell line cultured on an equibiaxial stretch device has such characteristic. Because there is a recruitment and commitment of preosteoblastic cells during bone lengthening and no previous report has focus on them, the authors used a preosteoblast MC3T3-E1 cell line to detect the early molecular effects of distraction on mesenchymal cells. By using DNA microarrays containing 15,000 clones, the authors identified several genes the expression of which was significantly up- or down-regulated. The differentially expressed genes cover a broad range of biological processes: cell growth, metabolism, morphogenesis, cell communication, response to stress, and cell death. The data reported are the first genetic portrait of stretched preosteoblasts. They can be relevant in the better understanding of the molecular mechanism of DO and as a model for comparing the effect of distraction on different cell lines and primary cultures, rate and strength of distraction, and with or without cytokines.

3T3 Cells↗

PubMed2005

Clinical and histologic analysis of calcium sulfate in treatment of a post-extraction defect: a case report.

We report a case of a postextraction maxillary buccal dehiscence grafted with calcium sulfate to insert a dental implant. The clinical results were supported by histologic analysis of two specimens collected in the healed socket to better understand the biologic effects of calcium sulfate. A 42-year-old white female presented with an almost totally edentulous maxillary right arch with a wide postextraction defect in the canine region. Calcium sulfate mixed with sterile saline solution to a putty-like consistency was packed into the defect, and four dental implants were placed in the edentulous ridge. On re-entry, a dental implant and small amounts of calcium sulfate were placed in the grafted site. After 5 months, a specimen of the region implanted with calcium sulfate was retrieved for histologic evaluation. On surgical re-entry, a complete filling of the defect with mature, dense, newly formed bone occurred. Complete resorption of the grafted material and its substitution with newly formed bone tissue were confirmed by histologic analysis. All of the implants appeared to be osseointegrated successfully, and the patient was provided with a fixed implant-supported prosthesis. Calcium sulfate represents an aid in bone regeneration procedures.

Adult↗

PubMed2005

Maxillary sinus augmentation using a synthetic cell-binding peptide: a histologic and transmission electron microscopy case study in man.

PepGen P-15 is a combination natural anorganic bovine-derived hydroxyapatite matrix coupled with a synthetic cell-binding peptide (P-15). This material has improved bone formation in periodontal osseous defects and bone regenerative procedures. There were 3 specimens retrieved 18 months after a sinus lifting procedure using PepGen P-15. These specimens were treated to be observed under light microscopy and transmission electron microscopy. Light microscopy showed that most of the particles were surrounded by newly formed bone. In some areas, osteoid matrix was present. No acute inflammatory infiltrate was present. In transmission electron microscopy, all phases of bone formation (i.e., osteoid matrix, woven bone, and lamellar bone) were observed in the newly formed bone around the biomaterial particles. In some regions, this newly formed bone seemed to present interdigitations connecting to or entering into the particle surface. To our knowledge, this is the first report presenting data on transmission electron microscopy of PepGen P-15 used in a sinus augmentation procedure in man. Our results confirm previous reports on the clinical effectiveness of this material.

Alveolar Ridge Augmentation↗

PubMed2005

Haemangiopericytoma of the maxillary gingiva: report of a case.

AIM: Haemangiopericytoma (HPC) represents approximately 3% of all tumours in the head and neck. This tumour is a soft tissue tumour derived from mesenchymal cells with pericytic differentiation. We present the clinicopathological findings of a case. MATERIALS AND METHODS: A 69-year-old man was referred to our Department for a mass located on the right pre-molar maxillary gingiva; this mass caused problems during chewing, but was otherwise asymptomatic. RESULTS: Clinical examination revealed a nodular, pink lesion, 3.5 cm in diameter, which was lined with normal mucosa. The lesion was mobile in relation to the deep and superficial tissues. Microscopic analysis of the neoplasm showed a vascular rich pattern, constituted by vessels covered with flat endothelium and surrounded by abundant spindly cells. On the basis of these histological and immunohistochemical findings, the final diagnosis was HPC. CONCLUSIONS: HPC is an uncommon vascular tumour for which the biological behaviour is difficult to predict. In our patient, no recurrences or distant metastases were present at a 4 years follow-up.

Aged↗