The Effect of Diclofenac Sodium-Loaded Poly(Lactide-co-Glycolide) Rods on Bone Formation and Inflammation: A Histological and Histomorphometric Study in the Femora of Rats

Implants made of poly(lactide-co-glycolide) (PLGA) are biodegradable and frequently provoke foreign body reactions (FBR) in the host tissue. In order to modulate the inflammatory response of the host tissue, PLGA implants can be loaded with anti-inflammatory drugs. The aim of this study was to analyze the impact of PLGA 80/20 rods loaded with the diclofenac sodium (DS) on local tissue reactions in the femur of rats. Special emphasis was put on bone regeneration and the presence of multinucleated giant cells (MGCs) associated with FBR. PLGA 80/20 alone and PLGA 80/20 combined with DS was extruded into rods. PLGA rods loaded with DS (PLGA+DS) were implanted into the femora of 18 rats. Eighteen control rats received unloaded PLGA rods. The follow-up period was of 3, 6 and 12 weeks. Each group comprised of six rats. Peri-implant tissue reactions were histologically and histomorphometrically evaluated. The implantation of PLGA and PLGA+DS8 rods induced the formation of a layer of newly formed bone islands parallel to the contour of the implants. PLGA+DS rods tended to reduce the presence of multi-nucleated giant cells (MGCs) at the implant surface. Although it is known that the systemic administration of DS is associated with compromised bone healing, the local release of DS via PLGA rods did not have negative effects on bone regeneration in the femora of rats throughout 12 weeks

Oral bone loss and its implications for prosthetics and dental implant therapy : influences of advanced age and the anatomical jaw region

Mund- und Zahnerkrankungen zählen zu den häufigsten chronischen Krankheiten weltweit. Sie sind speziell unter der älteren Bevölkerung prävalent. Unbehandelt führen sie häufig zu einer Reduktion des Kieferknochens und Zahnverlust - zwei pathologische Zustände, die schwerwiegende Folgen für die betroffenen Individuen haben und Gesundheitssysteme schwer belasten. Trotz signifikanter Fortschritte in Bereich der Mund- und Zahngesundheit in den vergangenen Jahren, stellen orale Erkrankungen ein großes globales Problem dar. Forschungsschwerpunkte im Bereich Risiko-Identifikation sowie Untersuchung von Krankheitsmechanismen und sozioökonomischen und epidemiologischen Entwicklungen sind erforderlich, um orale Erkrankungen erfolgreich entgegenwirken zu können. Basierend auf diesem Hintergrund war das Ziel dieser Dissertation, strukturelle, pathologische und Regenerations-assoziierte Veränderungen des Kieferknochens im Zuge von Krankheit und des Alterns zu untersuchen. Der Fokus wurde auf drei kontrovers diskutierte Aspekte im Zusammenhang mit oralem Knochenverlust gelegt: (a) Die erste Studie beschäftigte sich mit der Frage, ob Kieferatrophie als Folge von prothetischem Zahnersatz oder unabhängig von diesem auftritt. Um den vielfach beschriebenen potentiellen negativen Effekt von schlecht-sitzenden Zahnprothesen auszuschließen, wurde ein historisches Sample untersucht, das keinen Zugang zu moderner Prothetik hatte. Makroskopische Merkmale von Kieferatrophie und Knochendegradation wurden mittels adaptiertem Klassifikationssystem nach Atwood und Cawood & Howell ausgewertet. Die Ergebnisse zeigten, dass Atrophie auch in Abwesenheit von prothetischer Behandlung auftritt und einen gleichen Verlauf nimmt wie bei modernen Populationen beschrieben. Die Ausprägung des Knochenverlustes ist mit dem Alter der Individuen sowie der Region innerhalb des Kiefers assoziiert. (b) In der zweiten Studie wurde untersucht, ob und in welchem Ausmaß Osteoporose die Kortikalis des Kieferknochens im Schaf beeinflusst. Ziel dabei war, ein präklinisches Model zu etablieren, das die Verhältnisse beim osteoporotischen Patienten simuliert. Auf diese Weise könnten grundlegende Erkenntnisse über den Einfluss der Porosität der Kortikalis auf die Implantatstabilität gewonnen werden. Osteoporose wurde durch Ovarektomie, Glucocorticoid-Applikation sowie einer Kalzium/Vitamin D reduzierten Diät induziert. Histologische Schliffe der Mandibeln wurden histomorphometrisch ausgewertet und zeigten eine signifikante Erhöhung der kortikalen Porosität in geriatrischen osteoporotischen Schafen im Vergleich zu adulten Kontrollschafen. Die Ausprägung des kortikalen Knochenverlustes war mit der Region innerhalb des Kiefers assoziiert. (c) Die dritte Studie untersuchte Faktoren, welche die Knochenregeneration nach Sinus Augmentation beeinträchtigen. Humane Sinus-Biopsien wurden 61 Monate nach Sinus Augmentation entnommen und histomorphometrisch ausgewertet. Fortgeschrittenes Alter bei Frauen sowie ein reduziertes lokales Knochenangebot verminderten das Regenerationspotenzial des Knochens. Die Menge an Knochenneubildung und die Integration des Knochenersatzmaterials war in diesen Fällen signifikant reduziert. Zusammengefasst geben unsere Daten Einblick in die Vielfältigkeit von oralem Knochenverlust. Einige Aspekte der komplexen Zusammenhänge zwischen Zahnverlust, Kieferatrophie, Osteoporose und dem Knochenregenerationspotenzial wurden präsentiert. Viele weiter Faktoren bedürfen jedoch weiterer führender Untersuchungen, um deren Einfluss auf die oben beschrieben Erkrankungen zu verstehen. Die Kenntnis von Alters- und Krankheits-bedingten Veränderungen in Physiologie und Struktur des Kieferknochens können dazu beitragen, optimierte, holistische und Evidenz-basierte Behandlungsstrategien zu entwickeln.Oral diseases are among the most common chronic diseases worldwide. They are particularly prevalent in the elderly population and without appropriate treatment frequently result in the loss of oral bone and teeth - two pathological conditions that have far-reaching consequences for the affected individual as well as for healthcare systems. Despite significant advances in oral health in recent years, oral diseases remained a major global burden. Thus, particular attention in medical research must be drawn to the identification of risk factors as well as the understanding of disease mechanisms and of socioeconomic and epidemiologic developments. Based on this background, this doctoral thesis aimed to investigate structural, pathological and regeneration- associated alterations of the jawbone in the course of disease and aging. We thereby addressed the following three controversially discussed aspects related to oral bone loss: (a) Within the first study, we explored the question of whether jaw atrophy following tooth loss also occurs in the absence of prosthetic treatment. To exclude the frequently described potentially negative effect of ill-fitting dentures, we studied an historical sample that had no access to any kind of modern prosthetics. Atrophy was macroscopically assessed according to an adapted classification system of Atwood and Cawood & Howell. In fact, atrophy did occur in absence of denture treatment and showed a similar pattern of bone loss as described for modern populations. Severity of bone loss was associated with individual's age and the jaw region. (b) Secondly, it was investigated whether and to what extent osteoporosis affects the cortical compartment of jawbone in sheep. We thereby aimed to introduce a preclinical model that closely mimics the situation in osteoporotic patients and thus might provide a basis for the investigation of the impact of cortical porosity on implant stability. To induce osteoporosis, sheep were subjected to ovariectomy, glucocorticoid treatment and calcium/vitamin D restricted diet. Histomorphometric evaluation of mandibular sections revealed that cortical porosity was significantly increased in geriatric sheep compared to healthy adult control sheep. Severity of bone loss showed site-specific differences. (c) Thirdly, we examined which factors might contribute to impaired bone regeneration after sinus augmentation. Human sinus biopsies harvested 61 months after sinus augmentation were subjected to histomorphometric analysis. Advanced age in women and decreased local bone supply were identified to significantly impair the bone regeneration potential in terms of new bone formation and integration of bone substitute. In conclusion, our data give an insight in to the multifaceted nature of oral bone loss. Several aspects of the complex interrelationship between tooth loss, jaw atrophy, osteoporosis and the bone regeneration potential were presented. But still many influences are far from being thoroughly understood. Based on the knowledge of age- and disease-related alterations in physiology and structure of the jawbone, optimised, more holistic and evidence based treatment strategies might be developed in future.submitted by Karoline M. ReichZsfassung in dt. SpracheWien, Med. Univ., Diss., 2011OeBB(VLID)188352

Osteocyte lacunar density and area in newly formed bone of the augmented sinus

OBJECTIVES Osteocytes, the most common cells of the bone, are buried in lacunae. Density and area of the osteocyte lacunae change with increasing maturation of the newly formed bone. Evaluation of osteocyte lacunae can therefore provide insights into the process of graft consolidation. MATERIALS AND METHODS Here, we determined the osteocyte lacunar density (number of osteocyte lacunae per bone area; N.Ot/BAr) and the osteocyte lacunar area in μm(2) (Lac.Ar) in histological specimens 6 and 12 weeks after the sinuses of 10 minipigs were augmented with Bio-Oss(®) , a deproteinized bovine bone mineral, and Ostim(®) , an aqueous paste of synthetic nanoparticular hydroxyapatite. The region of interest was defined by the following criteria: (i) >1 mm from the host bone, (ii) >0.5 mm from the sinus mucosa, (iii) minimum area of 0.2 mm(2) , and (iv) bone tissue spanning at least two bone substitute particles. RESULTS The overall osteocyte lacunar density was significantly higher in the Bio-Oss(®) group than in the Ostim(®) group and decreased during the observation period at a similar range in both groups. The osteocyte lacunar area was smaller in the Bio-Oss(®) group than the Ostim(®) group but there was no significant change within the groups over time. CONCLUSIONS These results suggest that bone substitutes affect the osteocyte lacunar density and the osteocyte lacunar area in the newly formed bone within the augmented sinus in this particular model situation. These measures can provide insights into the maturation of newly formed bone in the augmented sinus

Bone Graft Packing and Its Association with Bone Regeneration in Maxillary Sinus Floor Augmentations: Histomorphometric Analysis of Human Biopsies

Research in maxillary sinus floor augmentation (MSFA) focussed on the optimisation of microstructural parameters such as microporosity and particle size of bone substitute particles (BS). However, little is known about the impact of BS packing and the corresponding (void) interparticular space on bone regeneration. The aim of this study was to characterise the spatial distribution of BS and its association with BS integration 6 ± 1 months after MSFA. Histological thin-ground sections of 70 human sinus biopsies were histomorphometrically analysed: In serial zones of 100 µm proceeding from the sinus floor (SF) up to the apical end of the biopsy, we measured the distribution of BS particles within these zones in terms of volume (BSV/TV), number and size of BS particles, interparticle spacing (BS.Sp) and bone-to-BS contact. BS particles were not homogeneously distributed over the length of biopsies: The first 200 µm directly adjacent to the SF represented a zone poor in BS particles but with high osteogenic potential. Graft packing density increased from the SF towards the apical part of the AA. Integration of BS particles was inversely associated with the distance to the SF and the graft packing density. A high packing density through excessive compaction of BS particles should be avoided to optimise the macrostructural environment for bone regeneration

Effect of recombinant PDGF-BB on bone formation in the presence of β-tricalcium phosphate and bovine bone mineral matrix: a pilot study in rat calvarial defects.

BACKGROUND Supplementation of bone substitutes with recombinant platelet-derived growth factor-BB (PDGF-BB) can enhance bone regeneration. The aim of the study was to evaluate the effect of PDGF-BB on bone formation in the presence of β-tricalcium phosphate and bovine bone mineral matrix in a rat calvaria defect model. METHODS The authors examined 5 mm rat calvarial defects treated with β-tricalcium phosphate (TCP) or demineralized bovine bone mineral (DBBM) with and without 0.3 mg/ml recombinant PDGF-BB. Calvaria defects were randomly divided into the following treatment groups (n = 5); TCP; TCP plus PDGF-BB; DBBM; DBBM plus PDGF-BB; and untreated empty control. After 45 days, bone formation was evaluated by histomorphometry and fluorescence microscopy. RESULTS The authors report that the area of newly formed bone was similar between the empty controls and the two bone substitutes, TCP and DBBM. Supplementation of TCP and DBBM with PDGF-BB had no significant impact on bone formation. Fluorochrome staining revealed no visible changes in the pattern of bone formation in defects filled with TCP and DBBM, irrespective of PDGF-BB. Furthermore, supplementation with PDGF-BB did not influence biomaterial degradation. CONCLUSIONS The authors concluded that PDGF-BB had no impact on bone formation and degradation of bone substitutes in the respective rodent models. Thus, possible beneficial effects of PDGF-BB may require other model situations

The effect of diclofenac sodium-loaded poly(lactide-co-glycolide) rods on bone formation and inflammation:a histological and histomorphometric study in the femora of rats

Abstract Implants made of poly(lactide-co-glycolide) (PLGA) are biodegradable and frequently provoke foreign body reactions (FBR) in the host tissue. In order to modulate the inflammatory response of the host tissue, PLGA implants can be loaded with anti-inflammatory drugs. The aim of this study was to analyze the impact of PLGA 80/20 rods loaded with the diclofenac sodium (DS) on local tissue reactions in the femur of rats. Special emphasis was put on bone regeneration and the presence of multinucleated giant cells (MGCs) associated with FBR. PLGA 80/20 alone and PLGA 80/20 combined with DS was extruded into rods. PLGA rods loaded with DS (PLGA+DS) were implanted into the femora of 18 rats. Eighteen control rats received unloaded PLGA rods. The follow-up period was of 3, 6 and 12 weeks. Each group comprised of six rats. Peri-implant tissue reactions were histologically and histomorphometrically evaluated. The implantation of PLGA and PLGA+DS8 rods induced the formation of a layer of newly formed bone islands parallel to the contour of the implants. PLGA+DS rods tended to reduce the presence of multi-nucleated giant cells (MGCs) at the implant surface. Although it is known that the systemic administration of DS is associated with compromised bone healing, the local release of DS via PLGA rods did not have negative effects on bone regeneration in the femora of rats throughout 12 weeks

Neurodevelopmental Outcome and Health-related Quality of Life in Children With Single-ventricle Heart Disease Before Fontan Procedure

Neurodevelopmental impairment and impaired quality of life constitute a major source of morbidity among children with complex congenital heart disease, in particular for single-ventricle (SV) morphologies. Risk factors and quality of life determining clinical and neurodevelopmental outcome at 2 years of age are examined. In a 2-center cohort study, 48 patients with SV morphology (26 hypoplastic left heart syndrome and 22 other types of univentricular heart defect) have been examined before Fontan procedure between 2010 and 2015. Patients were assessed with the Bayley Scales of Infant and Toddler Development, Third Version (Bayley-III), and the Preschool Children Quality of Life (TAPQOL) questionnaire. A total of 44 patients underwent hybrid procedure (n = 25), Norwood procedure (n = 7), or shunt or banding procedure (n = 12) as first surgery before subsequent bidirectional cavopulmonary anastomosis (n = 48). Median cognitive, language, and motor composite scores on the Bayley-III were 100 (range 65-120), 97 (68-124), and 97 (55-124), respectively. The language composite score was significantly below the norm (P = 0.025). Risk factors for poorer neurodevelopmental outcome were prolonged mechanical ventilation, longer days of hospital stay, and more reinterventions (all P < 0.05). Parents reported a good quality of life for their children. Children undergoing Fontan procedure show a favorable development and good quality of life. More complicated postoperative course and reinterventions constitute risk factors for impaired neurodevelopment. Improving postoperative management and implementing routine follow-up assessments aremeasures to further improve the neurodevelopmental outcome of this high-risk patient population

Health-related quality of life in pre-school age children with single-ventricle CHD

BACKGROUND: Little is known about health-related quality of life in young children undergoing staged palliation for single-ventricle CHD. The aim of this study was to assess the impact of CHD on daily life in pre-schoolers with single-ventricle CHD and to identify determinants of health-related quality of life. METHOD: Prospective two-centre cohort study assessing health-related quality of life using the Preschool Paediatric Cardiac Quality of Life Inventory in 46 children at a mean age of 38 months and 3 weeks. Children with genetic anomalies were excluded. Scores were compared with reference data of children with biventricular CHD. Multiple linear regression analysis was used to identify determinants of health-related quality of life. RESULTS: Health-related quality of life in pre-schoolers with single-ventricle CHD was comparable to children with biventricular CHD. Preterm birth and perioperative variables were significant predictors of low health-related quality of life. Notably, pre-Fontan brain MRI findings and neurodevelopmental status were not associated with health-related quality of life. Overall, perioperative variables explained 24% of the variability of the total health-related quality of life score.InterpretationDespite substantial health-related burden, pre-schoolers with single-ventricle CHD showed good health-related quality of life. Less-modifiable treatment-related risk factors and preterm birth had the highest impact on health-related quality of life. Long-term follow-up assessment of self-reported health-related quality of life is needed to identify patients with poorer health-related quality of life and to initiate supportive care