The analysis of anatomic variations of sphenoid sinus with the use of CBCT technology

Sfenoidni sinus najvarijabilnija je šupljina ljudskog tijela. Unatoč tome što su u literaturi opisane brojne varijacije sfenoidnog sinusa gotovo je potpuno neistraženo ovisi li učestalost pneumatizacije drugih dijelova sfenoidne kosti i protruzija žilno-živčanih struktura o tipu pneumatizacije sinusa. Cilj istraživanja je odrediti učestalost pneumatizacije ala major, processusa pterygoideusa, planuma sphenoidalea, dorsuma sellae i clivusa te protruzija n.maxillarisa, n.canalis pterygoidei, n.opticusa, a.carotis interne i n.mandibularisa za sinuse pojedinih tipova pneumatizacije (conchalni, presellarni, sellarni, postsellarni). U istraživanju je korištena 51 lubanja koje su snimljene CBCT uređajem. Napravljen je novi sustav klasifikacije te su odnosi sinusa i žilno-živčanih struktura klasificirani u 5 kategorija. Pronađene su velike razlike između sinusa različitih tipova pneumatizacije. Učestalost pneumatizacije svih promatranih dijelova klinaste kosti kao i protruzija žilno-živčanih struktura značajno raste u nizu tipova sinusa: conchalni, presellarni, sellarni, postsellarni. Istraživanjem je dokazano kako se na osnovi tipa pneumatizacije može predvidjeti pružanje sinusa te odnosi sinusa s bliskim žilno-živčanim strukturama. Poznavanje navedenih činjenica može biti važno radi sprječavanja mogućih komplikacija tijekom kirurških zahvata te radi razumijevanja patogeneze procesa koji mogu imati ishodište u sfenoidnom sinusu.Sphenoid sinus is the most variable cavity in the human body. The aim of the study has been to determine the frequency of pneumatization of greater wings, pterygoid process, planum sphenoidalae, dorsum sellae and clivus, as well as the protrusions of maxillary nerve, pterygoid nerve, optic nerve, internal carotid artery and mandibular nerve for the sinuses of certain types of pneumatization (conchal, presellar, sellar, postsellar). The total of 51 CBCT-recorded skulls has been used in the study. A new classification system has been suggested, so that the relations between sinuses and neurovascular structures have been classified into 5 categories. Big differences between sinuses of various types of pneumatization have been discovered. The frequency of pneumatization of all the analysed parts of the sphenoid bone and the protrusion of neurovascular structures significantly increases in a series of types: conchal, presellar, sellar, postsellar. The knowledge of the above-stated facts may be important for preventing potential complications in the course of operation and understanding the pathogenesis of processes that can result from sphenoid sinus

The analysis of anatomic variations of sphenoid sinus with the use of CBCT technology

Sfenoidni sinus najvarijabilnija je šupljina ljudskog tijela. Unatoč tome što su u literaturi opisane brojne varijacije sfenoidnog sinusa gotovo je potpuno neistraženo ovisi li učestalost pneumatizacije drugih dijelova sfenoidne kosti i protruzija žilno-živčanih struktura o tipu pneumatizacije sinusa. Cilj istraživanja je odrediti učestalost pneumatizacije ala major, processusa pterygoideusa, planuma sphenoidalea, dorsuma sellae i clivusa te protruzija n.maxillarisa, n.canalis pterygoidei, n.opticusa, a.carotis interne i n.mandibularisa za sinuse pojedinih tipova pneumatizacije (conchalni, presellarni, sellarni, postsellarni). U istraživanju je korištena 51 lubanja koje su snimljene CBCT uređajem. Napravljen je novi sustav klasifikacije te su odnosi sinusa i žilno-živčanih struktura klasificirani u 5 kategorija. Pronađene su velike razlike između sinusa različitih tipova pneumatizacije. Učestalost pneumatizacije svih promatranih dijelova klinaste kosti kao i protruzija žilno-živčanih struktura značajno raste u nizu tipova sinusa: conchalni, presellarni, sellarni, postsellarni. Istraživanjem je dokazano kako se na osnovi tipa pneumatizacije može predvidjeti pružanje sinusa te odnosi sinusa s bliskim žilno-živčanim strukturama. Poznavanje navedenih činjenica može biti važno radi sprječavanja mogućih komplikacija tijekom kirurških zahvata te radi razumijevanja patogeneze procesa koji mogu imati ishodište u sfenoidnom sinusu.Sphenoid sinus is the most variable cavity in the human body. The aim of the study has been to determine the frequency of pneumatization of greater wings, pterygoid process, planum sphenoidalae, dorsum sellae and clivus, as well as the protrusions of maxillary nerve, pterygoid nerve, optic nerve, internal carotid artery and mandibular nerve for the sinuses of certain types of pneumatization (conchal, presellar, sellar, postsellar). The total of 51 CBCT-recorded skulls has been used in the study. A new classification system has been suggested, so that the relations between sinuses and neurovascular structures have been classified into 5 categories. Big differences between sinuses of various types of pneumatization have been discovered. The frequency of pneumatization of all the analysed parts of the sphenoid bone and the protrusion of neurovascular structures significantly increases in a series of types: conchal, presellar, sellar, postsellar. The knowledge of the above-stated facts may be important for preventing potential complications in the course of operation and understanding the pathogenesis of processes that can result from sphenoid sinus

A simple rodent subcutaneous assay for identification of new osteoinductive molecules: The key method for screening of novel bone regeneration implants

Treatment of large bone defects and degenerative diseases of the spine is among the most challeng- ing and still unresolved issues in clinical medicine. Therefore, substantial effort has been devoted to the development of novel bone regenerative therapies. Due to their potent osteoinductive properties, Bone Morphogenetic Proteins (BMPs) have been the basis for the development of novel strategies for bone regeneration. The use of animal models is an indispensable part of the preclinical testing of novel therapeutic solutions. The rat subcutaneous assay became the initial screening procedure for the evalu- ation of promising BMP-based osteoinductive devices for bone regeneration because only osteogenic BMPs can induce new bone at any ectopic rodent site. Moreover, this model is used for research on the mechanisms of ectopic bone formation as well as for the evaluation of the inflammatory response to different materials. In this review, we provided an overview of the assay development and previously conducted studies with different methods (flow cytometry, histological and microCT analyses) for the study outcome evaluation. Moreover, we addressed essential issues in the experimental design such as the follow-up period and the sample size. The rat subcutaneous bone induction assay layed the founda- tion for isolation and identification of BMPs followed by testing of new osteogenic devices in higher animal species and humans

Interleukin-1beta gene promoter polymorphism is associated with higher liver fibrosis progression rate in Croatian patients with biochemically active chronic hepatitis C

Background and aims: Genetic polymorphisms of immune mediators have been associated with differences in the natural course of chronic hepatitis C (CHC). The aim of this study was to analyze the association of IL-1β gene polymorphism with the stage of liver fibrosis (LF), grade of necroinflammatory activity (NIA) and fibrosis progression rate (FPR) in CHC patients. Patients and methods: The study included 50 treatment-naive Croatian CHC patients (36 male and 14 female; age median 37.5 years) with elevated ALT. Diallele polymorphism (C/T) at locus -31 in the IL-1β gene promoter region was determined by restriction fragment length polymorphism (RFLP). Stage of LF and NIA were assessed from liver biopsy sample according to Ishak classification. Results: There was no difference in the stage of LF and NIA level between particular patient genotypes. However, patients with at least 1 C allele at locus -31showed significantly faster FPR than those with no C allele (0.4 vs. 0.258 Ishak\u27s units/year; p = 0.043). Higher stages of fibrosis were observed in older patients (p = 0.001) and those infected at an older age (p = 0.017). Conclusion: Our study demonstrated that the carriage of at least 1 C allele at -31 locus of IL-1β gene led to faster progression of LF in CHC patients with a biochemically active disease, but did not determine the final stage of fibrosis development. Combined with other risk factors, this finding may serve as a genetic marker to identify patients that require earlier introduction of therapy, since delay could hamper therapeutic success due to rapid disease progression

State-of-the-art of the Bone Morphogenetic Protein research field: 13th International BMP Conference, Dubrovnik 2022

The 13th International BMP Conference was held in October 2022 in Dubrovnik. The conference was attended by more than 240 participants from North America, Europe, Asia, and Australia who got an insight into the latest achievements in basic, translational, and clinical research of BMP mol- ecules through 75 lectures categorized into several scientific sections. This review paper provides the most important novel findings on the structure, function, and signaling of BMPs, the role of BMPs in patterning and organoids as well as the role of BMP in metabolism. Moreover, we discussed the role of BMPs in various diseases including cancer pathogenesis, pulmonary arterial hyperten- sion, and fibrodysplasia ossificans progressiva (FOP). Finally, we provided an overview of the new BMP-based therapies in regenerative medicine that are currently in different stages of preclinical and clinical trials

Autologous blood coagulum containing rhBMP6 induces new bone formation to promote anterior lumbar interbody fusion (ALIF) and posterolateral lumbar fusion (PLF) of spine in sheep

resent study, we evaluated an autologous bone graft substitute (ABGS) composed of recombinant human BMP6 (rhBMP6) dispersed within autologous blood coagulum (ABC) used as a physiological carrier for new bone formation in spine fusion sheep models. The application of ABGS included cervical cage for use in the anterior lumbar interbody fusion (ALIF), while for the posterolateral lumbar fusion (PLF) sheep model allograft devitalized bone particles (ALLO) were applied with and without use of instrumentation. In the ALIF model, ABGS (rhBMP6/ABC/cage) implants fused significantly when placed in between the denuded L4- L5 vertebrae as compared to control (ABC/cage) which appears to have a fibrocartilaginous gap, as examined by histology and micro CT analysis at 16 weeks following surgery. In the PLF model, ABGS implants with or without ALLO showed a complete fusion when placed ectopically in the gutter bilaterally between two decorticated L4-L5 transverse processes at a success rate of 88% without instrumentation and at 80% with instrumentation ; however the bone volume was 50% lower in the instrumentation group than without, as examined by histology, radiographs, micro CT analyses and biomechanical testing at 27 weeks following surgery. The newly formed bone was uniform within ABGS implants resulting in a biomechanically competent and histologically qualified fusion with an optimum dose in the range of 100 g rhBMP6 per mL ABC, while in the implants that contained ALLO, the mineralized bone particles were substituted by the newly formed remodeling bone via creeping substitution. These findings demonstrate for the first time that ABGS (rhBMP6/ABC) without and with ALLO particles induced a robust bone formation with a successful fusion in sheep models of ALIF and PLF, and that autologous blood coagulum (ABC) serves as a preferred physiological native carrier to induce new bone at low doses of rhBMP6 and to achieve a successful spinal fusion

Koštani morfogenetski proteini (BMP): Od otkrića do razvoja nove autologne koštane naprave koja se sastoji od rekombinantnog humanog BMP6 u autolognom krvnom ugrušku kao nosaču

Bone Morphogenetic Proteins (BMPs) are growth and differentiation factors within the TGFβ superfam- ily of proteins. They induce ectopic and orthotopic endochondral bone formation and are involved in the regulation of cell proliferation, differentiation, apoptosis and mesenchymal-epithelial interactions in critical morphogenetic processes of tissues beyond bone. BMP2 and BMP7 osteogenic devices have been approved for enhancing healing in patients with long bone defects and anterior spinal fusion proce- dures. However, due to a high price and various serious adverse events including heterotopic ossifica- tion, retrograde ejaculation and pain their clinical use have been limited. In this review we discuss the BMP discovery, biology and their use in clinical studies with particular reference to the newly developed BMP6 based autologous bone graft substitute (ABGS). A novel ABGS consisting of an autologous bone coagulum (ABC) carrier with dispersed BMP6 to initiate the differentiation of mesenchymal cells into endochondral bone. The ABC met the conditions for an optimal delivery system for BMP6 due to han- dling simplicity, without an immunogenic and inflammatory response at the implantation site. Addition of allograft or synthetic ceramics to ABGS demonstrated in animal models significantly increased volume and better microarchitecture of the newly formed bone. The first clinical study was conducted in patients with distal radial fractures (Phase I study) and the second in patients undergoing high tibial osteotomy (Phase I/II study) and no serious adverse events have been observed. Finally, in the ongoing OSTEO- proSPINE study ABGS enforced with allograft bone is evaluated in patients with chronic back pain due to degenerative disc diseases. The novel ABGS bone mimetic is a major breakthrough and contribution to bone biology and regenerative medicine of skeletal repair.Koštani morfogenetski proteini (BMP) čine grupu čimbenika rasta i diferencijacije unutar TGFβ nado- bitelji. Oni induciraju stvaranje ektopične i ortotopične endohondralne kosti te su uključeni u regulaciju stanične proliferacije, diferencijacije, apoptoze i mezenhimalno-epitelne interakcije u važnim tkivnim morfogenetskim procesima izvan koštanog sustava. Koštane naprave koje sadrže BMP2 i BMP7 pro- tein odobrene su za poboljšanje koštanog cijeljenja kod pacijenata s defektima dugih cjevastih kostiju i kod prednje spinalne fuzije kralježnice. Međutim, zbog visoke cijene i mnogobrojnih nuspojava koje su uključivale pojavu heterotopičnih osifikacija, retrogradnu ejakulaciju i bol, njihova je klinička prim- jena ograničena. U ovom smo preglednom radu raspravili otkriće BMP molekula, njihovu biologiju i primjenu u kliničkim studijama s posebnim osvrtom na nedavno otkrivenu novu autolognu koštanu napravu (ABGS) koja sadrži BMP6. Novi ABGS sastoji se od nosača autolognog koaguluma (ABC) s otopljenim BMP6 koji je ključan za pokretanje diferencijacije mezenhimalnih stanica u smjeru stvaranja endohondralne kosti. ABC je ispunio sve potrebne uvjete za formulaciju optimalnog nosača za BMP6 isključivo zbog jednostavnosti priprave i primjene te odsustva imunogenog i upalnog odgovora na mjestu implantacije. Uz dodatak alografta ili sintetičke keramike što je potvrđeno na životinjskim modelima došlo je do značajnog povećanja volumena te poboljšanja mikroarhitekture novonastale kosti. Prvo kliničko ispitivanje provedeno je na pacijentima s distalnim prijelomima radijusa (faza I studije), a drugo na pacijentima koji su podvrgnuti visokoj osteotomiji tibije (faza I/II studije) bez uočenih ozbiljnih nuspojava. Trenutno je u tijeku studija OSTEOproSPINE u kojoj se testira učinkovitost ABGS u kom- binaciji s koštanim alograftom u bolesnika s kroničnim bolovima u leđima uzrokovanim degenerativnim promjenama intervertebralnog diska. Nova ABGS koštana naprava značajna je prekretnica i napredak u području koštane biologije te regenerativne medicine koštanog sustava

The analysis of anatomic variations of sphenoid sinus with the use of CBCT technology

Sfenoidni sinus najvarijabilnija je šupljina ljudskog tijela. Unatoč tome što su u literaturi opisane brojne varijacije sfenoidnog sinusa gotovo je potpuno neistraženo ovisi li učestalost pneumatizacije drugih dijelova sfenoidne kosti i protruzija žilno-živčanih struktura o tipu pneumatizacije sinusa. Cilj istraživanja je odrediti učestalost pneumatizacije ala major, processusa pterygoideusa, planuma sphenoidalea, dorsuma sellae i clivusa te protruzija n.maxillarisa, n.canalis pterygoidei, n.opticusa, a.carotis interne i n.mandibularisa za sinuse pojedinih tipova pneumatizacije (conchalni, presellarni, sellarni, postsellarni). U istraživanju je korištena 51 lubanja koje su snimljene CBCT uređajem. Napravljen je novi sustav klasifikacije te su odnosi sinusa i žilno-živčanih struktura klasificirani u 5 kategorija. Pronađene su velike razlike između sinusa različitih tipova pneumatizacije. Učestalost pneumatizacije svih promatranih dijelova klinaste kosti kao i protruzija žilno-živčanih struktura značajno raste u nizu tipova sinusa: conchalni, presellarni, sellarni, postsellarni. Istraživanjem je dokazano kako se na osnovi tipa pneumatizacije može predvidjeti pružanje sinusa te odnosi sinusa s bliskim žilno-živčanim strukturama. Poznavanje navedenih činjenica može biti važno radi sprječavanja mogućih komplikacija tijekom kirurških zahvata te radi razumijevanja patogeneze procesa koji mogu imati ishodište u sfenoidnom sinusu.Sphenoid sinus is the most variable cavity in the human body. The aim of the study has been to determine the frequency of pneumatization of greater wings, pterygoid process, planum sphenoidalae, dorsum sellae and clivus, as well as the protrusions of maxillary nerve, pterygoid nerve, optic nerve, internal carotid artery and mandibular nerve for the sinuses of certain types of pneumatization (conchal, presellar, sellar, postsellar). The total of 51 CBCT-recorded skulls has been used in the study. A new classification system has been suggested, so that the relations between sinuses and neurovascular structures have been classified into 5 categories. Big differences between sinuses of various types of pneumatization have been discovered. The frequency of pneumatization of all the analysed parts of the sphenoid bone and the protrusion of neurovascular structures significantly increases in a series of types: conchal, presellar, sellar, postsellar. The knowledge of the above-stated facts may be important for preventing potential complications in the course of operation and understanding the pathogenesis of processes that can result from sphenoid sinus

Ectopic bone induction by osteoinductive device composed of recombinant human bone morphogenetic protein 6 (rhBMP6), autologous blood coagulum and biphasic bioceramics

Osteoinduktivni lijek koji sadrži rekombinantni humani koštani morfogenetski protein 6 (rhBMP6) u autolognom krvnom ugrušku (ABC) s biokeramičkim česticama, nova je terapijska opcija za postizanje spinalne fuzije i liječenje segmentalnih defekata dugih kostiju. U sklopu ovog rada istražena je biologija i vremenski tijek ektopičnog stvaranja koštanog tkiva pod utjecajem rhBMP6 u ABC-u s biokeramičkim česticama različite veličine (74-420 μm, 500-1700 μm i 2360-4000 μm) na modelu subkutane ugradnje implantata u štakora. Time je dokazana sigurnost i efikasnost osteoinduktivnog lijeka na modelu posterolateralne spinalne fuzije (PLF) kod kunića. Biokeramičke čestice promoviraju stvaranje kosti pod utjecajem rhBMP6 u subkutanom eseju kod štakora, a veličina čestica determinira mehanizam osifikacije, strukturu i dugotrajnost kosti. U implantatima s malim biokeramičkim česticama koje imaju veliku površinu i male udaljenosti između čestica, kost nastaje predominantno intramembranozno, a u implantatima sa srednjim i velikim česticama predominantno endokondralno. Novostvorena koštano-keramička struktura s malim česticama sastoji se od gustog koštanog tkiva na površini i između čestica, s limitiranom koštanom srži te se njegova struktura ne mijenja u vremenu. Koštano-keramička struktura sa srednjim i velikim česticama sastoji se od kortikalne kosti i kosti na površini čestica koje su postojane u vremenu, te trabekula između čestica čija se debljina smanjuje u vremenu. U modelu PLF-a kod kunića dokazano je da osteoinduktivni lijek (rhBMP6/ABC) s biokeramičkim česticama inducira stvaranje kosti koja se uspješno fuzionira s nativnim transverzalnim nastavcima. Navedena je spoznaja polazna točka za daljnja istraživanja kojima je cilj razvoj lijeka za kliničku primjenu.Osteoinductive device comprised of recombinant human Bone Morphogenetic Protein 6 (rhBMP6) in autologous blood coagulum (ABC) with bioceramic particles is a novel therapeutic solution for spinal fusions and management of segmental bone defects. In this study we elucidated biology and time course of ectopic bone formation induced by rhBMP6 in ABC with bioceramic particles of different sizes (74-420 μm, 500-1700 μm and 2360-4000 μm) using rat subcutaneous implant assay. Moreover, we have proven safety and efficacy of osteoinductive device in rabbit PLF model. Bioceramic particles promoted rhBMP6 mediated bone formation in rat subcutaneous assay while particle size determined mechanism of ossification, structure and longevity of newly formed bone. In implants containing small particles which are characterized by large surfaces and small distances between the particles, bone was predominantly formed through intramembranous pathway while in implants containing medium and large ceramics bone was predominantly formed endochondrally. Newly formed bone-ceramic structure (BCS) with small particles contained dense bone between the particles and its structure was constant in time. BCS with medium and large particles contained cortical bone and bone at the surfaces of particles which were constant in time and trabeculae between the particles which decreased in time. In the rabbit PLF model it was demonstrated that osteoinductive device (rhBMP6/ABC) with bioceramic particles induces bone formation and osseointegration with native transverse processes. Findings of this study will be the basis for further research aimed to developing a drug for clinical use

Ectopic bone induction by osteoinductive device composed of recombinant human bone morphogenetic protein 6 (rhBMP6), autologous blood coagulum and biphasic bioceramics

Osteoinduktivni lijek koji sadrži rekombinantni humani koštani morfogenetski protein 6 (rhBMP6) u autolognom krvnom ugrušku (ABC) s biokeramičkim česticama, nova je terapijska opcija za postizanje spinalne fuzije i liječenje segmentalnih defekata dugih kostiju. U sklopu ovog rada istražena je biologija i vremenski tijek ektopičnog stvaranja koštanog tkiva pod utjecajem rhBMP6 u ABC-u s biokeramičkim česticama različite veličine (74-420 μm, 500-1700 μm i 2360-4000 μm) na modelu subkutane ugradnje implantata u štakora. Time je dokazana sigurnost i efikasnost osteoinduktivnog lijeka na modelu posterolateralne spinalne fuzije (PLF) kod kunića. Biokeramičke čestice promoviraju stvaranje kosti pod utjecajem rhBMP6 u subkutanom eseju kod štakora, a veličina čestica determinira mehanizam osifikacije, strukturu i dugotrajnost kosti. U implantatima s malim biokeramičkim česticama koje imaju veliku površinu i male udaljenosti između čestica, kost nastaje predominantno intramembranozno, a u implantatima sa srednjim i velikim česticama predominantno endokondralno. Novostvorena koštano-keramička struktura s malim česticama sastoji se od gustog koštanog tkiva na površini i između čestica, s limitiranom koštanom srži te se njegova struktura ne mijenja u vremenu. Koštano-keramička struktura sa srednjim i velikim česticama sastoji se od kortikalne kosti i kosti na površini čestica koje su postojane u vremenu, te trabekula između čestica čija se debljina smanjuje u vremenu. U modelu PLF-a kod kunića dokazano je da osteoinduktivni lijek (rhBMP6/ABC) s biokeramičkim česticama inducira stvaranje kosti koja se uspješno fuzionira s nativnim transverzalnim nastavcima. Navedena je spoznaja polazna točka za daljnja istraživanja kojima je cilj razvoj lijeka za kliničku primjenu.Osteoinductive device comprised of recombinant human Bone Morphogenetic Protein 6 (rhBMP6) in autologous blood coagulum (ABC) with bioceramic particles is a novel therapeutic solution for spinal fusions and management of segmental bone defects. In this study we elucidated biology and time course of ectopic bone formation induced by rhBMP6 in ABC with bioceramic particles of different sizes (74-420 μm, 500-1700 μm and 2360-4000 μm) using rat subcutaneous implant assay. Moreover, we have proven safety and efficacy of osteoinductive device in rabbit PLF model. Bioceramic particles promoted rhBMP6 mediated bone formation in rat subcutaneous assay while particle size determined mechanism of ossification, structure and longevity of newly formed bone. In implants containing small particles which are characterized by large surfaces and small distances between the particles, bone was predominantly formed through intramembranous pathway while in implants containing medium and large ceramics bone was predominantly formed endochondrally. Newly formed bone-ceramic structure (BCS) with small particles contained dense bone between the particles and its structure was constant in time. BCS with medium and large particles contained cortical bone and bone at the surfaces of particles which were constant in time and trabeculae between the particles which decreased in time. In the rabbit PLF model it was demonstrated that osteoinductive device (rhBMP6/ABC) with bioceramic particles induces bone formation and osseointegration with native transverse processes. Findings of this study will be the basis for further research aimed to developing a drug for clinical use