Academic literature on the topic 'Injectable bone filler'

Abstract. Introduction: Current methods of managing osteomyelitic voids after debridement are inadequate and result in significant morbidity to patients. Synthetic ceramic void fillers are appropriate for non-infected bone defects but serve as a nidus of re-infection in osteomyelitis after debridement. CERAMENT G (CG) is an injectable ceramic bone void filler which contains gentamicin and is currently being evaluated for use in osteomyelitic environments after debridement due to its theoretical ability to serve as a scaffold for healing while eliminating residual bacteria after debridement through the elution of antibiotics. The goal of this study was to evaluate (1) the rate of persistent infection and (2) new bone growth of a debrided osteomyelitic defect in a rat model which has been treated with either gentamicin-impregnated ceramic cement (CERAMENT G) or the same void filler without antibiotics (CERAMENT, CBVF). Methods: Osteomyelitis was generated in the proximal tibia of Sprague Dawley rats, subsequently debrided, and the defect filled with either (1) CG (n=20), (2) CBVF (n=20), or (3) nothing (n=20). Each group was euthanized after 6 weeks. Infection was detected through bacterial culture and histology. Bone growth was quantified using microCT. Results: Infection was not detected in defects treated with CG as compared with 35 % of defects (7/20) treated with CBVF and 50 % (10/20) of empty defects (p=0.001). Bone volume in the defect of CG-treated rats was greater than the CBVF (0.21 vs. 0.17, p=0.021) and empty groups (0.21 vs. 0.11, p<0.001) at 6 weeks after implantation. Conclusions: Ceramic void filler with gentamicin (CERAMENT G) decreased the rate of persistent infection and increased new bone growth as compared to the same void filler without antibiotics (CERAMENT) and an empty defect in a rat model of debrided osteomyelitis.

We present a rare case of calcaneal chondroblastoma with subsequent surgical revision after graft rejection in a 13-year-old boy. Complications were encountered after the injectable bone graft filler was placed in the calcaneus after curettage. With noted subsequent sinus tract formation, revision surgery was performed that involved dissection of the sinus tract, removal of bone void filler, and application of demineralized bone matrix sponge human allograft soaked in vancomycin-impregnated saline. Sixteen weeks after the revision surgical intervention, the patient resumed normal athletic activities without pain or restrictions. One and a half years after the initial surgery, the patient had complete resolution of the calcaneal cyst and was discharged.

(1) Background: The tissue engineering field has been working to find biomaterials that mimic the biological properties of autogenous bone grafts. (2) Aim: To evaluate the osteoconduction potential of injectable calcium phosphate cement implanted in critical defects in rat calvaria. (3) Methods: In the calvarial bone of 36 rats, 7-mm diameter critical size defects were performed. Afterwards, the animals were randomly divided into three groups according to filler material: a blood clot group (BC), blood clot membrane group (BCM), and an injectable β-tricalcium phosphate group (HBS) cement group. After periods of 30 and 60 days, the animals were euthanized, the calvaria was isolated, and submitted to a decalcification process for later blades confection. Qualitative and quantitative analysis of the neoformed bone tissue were conducted, and histometric data were statistically analyzed. (4) Results: Sixty days post-surgery, the percentages of neoformed bone were 10.67 ± 5.57 in group BC, 16.71 ± 5.0 in group BCM, and 55.11 ± 13.20 in group HBS. The bone formation values in group HBS were significantly higher (p < 0.05) than in groups BC and BCM. (5) Conclusions: Based on these results, it can be concluded that injectable calcium phosphate cement is an osteoconductive material that can be used to fill bone cavities.

Injectable hydroxyapatite/collagen nanocomposite (HAp/Col) artificial bone was prepared utilizing gelation of sodium alginate (Na-Alg). Mass ratio of the HAp/Col powder, with or without Ca adsorption treatment and Na-Alg (80-120, 300-400, 500-600 cP in viscosity at 10 g/dm3) was fixed at 90/10. Injectable HAp/Col was prepared by mixing the HAp/Col powder with Na-Alg solution at several powder (HAp/Col)/liquid (Na-Alg solution) ratios (P/L ratio, g/cm3). The result of consistency measurement suggested that the operability of injectable HAp/Col paste could be controlled by both the P/L ratio and the viscosity of Na-Alg solution. According to the consistency measurement and practical feelings during mixing, P/L=1/1.67 (80-120 cP) and 1/1.89 (300-400, 500-600 cP) were considered to be the highest P/L ratio allowed to mix the HAp/Col paste with a spatula. At the P/L=1/2.33 (80-120 cP), the paste prepared with the non-treated HAp/Col powder, placed in an incubator (37 °C,relative humidity 100%) for 24h, demonstrated gel-like property, while the paste prepared with Ca-treated HAp/Col powder did putty-like property. The difference in their property might be caused by the initial bonding behavior between Alg and Ca2+ after mixing. The setting time measurement with Gillmore needle was impossible because they were toosoft for this method. Even though, their operability and coalescence/settingproperty could be used as the injectable bone filler.

An hydrated putty was prepared by mixing submicron particles, rounded particles and granules of Biphasic Calcium Phosphate (BCP) ceramics composed of HA and β-TCP phases. The material filled entirely critical sized defects in the femoral epiphysis of NZW rabbits. After 3, 6 and 12 weeks, histology revealed that submicron particles were rapidly degraded by multinucleated TRAP-positive cells. This osteoclastic resorption stimulated bone ingrowth while the large BCP particles served as scaffold supporting bone healing by osteoconduction.

Injectable resorbable bone cements for bone void fillings are gaining in interest. The materials resorb in vivo with loss of void filling capacity and strength as a consequence. The objective with this study is to qualitative determining the dissolution behaviour for a calcium sulphate and a calcium phosphate cement as function of storage time in different storage medium and correlate to their strength development. Experiments were performed on a calcium phosphate based cement, Norian SRS, and a calcium sulphate based cement, MIIG X3. In the resorbtion study, the materials dissolution at different pH (3, 5 and 7) was compared over a period of 11 weeks. The materials compressive and biaxial flexural strength was measured after aging in phosphate buffer saline for up to 12 weeks. The proposed qualitative method to study dissolution behaviour of injectable biomaterials as function of time and medium were evaluated and proved to be useful. Both materials were dissolved after 3 weeks of storage in pH 3. MIIG X3 dissolved faster than Norian SRS at pH 5. At pH 7 both materials were stable over the test period of 11 weeks. For both materials the strength decreases with storage time. Norian had a higher compressive strength than MIIG X3 for the first week, after the first week the compressive strength was similar for the two materials. MIIG X3 showed a higher flexural strength than Norian during the full test period.

AbstractBackground: CERAMENT™|BONE VOID FILLER is an injectable and moldable ceramic bone substitute material intended for bone voids. The material consists of hydroxyapatite and calcium sulfate hemihydrate. The aim of this study is to present the first long-term results following open curettage of benign bone tumors and tumor-like lesions and void filling with this novel injectable and synthetic bone graft. Methods: Thirty three patients were enrolled into the study between June 2013 and October 2014 .Totally, we treated 24 women and 9 men with a median age of 47 years (range: 22-74). All patients suffered from primary musculoskeletal system disorders (enchondroma 63,6%, giant cell tumor 18%, aneurysmal bone cyst 9%, fibrous dysplasia 9%, Gaucher disease 3%). We performed curettage of pathological lesions, then the bone substitute was administered by means of needle to the void. Results: The average follow-up was 13 months (range: 2-13 months, median 10 months). No metastasis or recurrence had been detected. We received significant clinical improvement relating to VAS, MSTS, and oncological results. Conclusions: The results of our study report that CERAMENT can be successfully used as a bone substitute in patients with various bone diseases, as well as benign bone tumors. CERAMENT can provide an effective and long-term solution for reconstructive procedures following curettage of bone tumors and tumor like lesions.

The synthesis of biocomposite (HA:TCP) – Gelatine – CMC for bone filler material has been carried out. In this research, the ratio of HA and TCP was varied as follows: 70:30, 50:50 and 40:60. The decrease of HA and the increase of TCP concentration will decrease the density, increase the percentage of porosity and swelling. The best composition for the synthesis was obtained for sample B with the ratio of HA:TCP = 50:50. For sample B, the synthesized biocomposite has the density of 1.67790 gr/cm3, porosity of 78.64%, tension of 10.14 MPa, swelling ability 46.85% and the sample mass degradation percentage of 8.1 %. The composition used for the biocomposite synthesis in this research was suitable to be applied as bone filler material which needs a dense pores and high tension.

2008/2009
La medicina rigenerativa applicata al campo ortopedico è considerata una possibile opzione terapeutica per la riparazione del tessuto osseo danneggiato. Si stanno studiano e sviluppando una gran varietà di sostituti ossei sintetici come valida alternativa agli innesti di tipo tissutale. Lo scopo di questo lavoro di tesi è la progettazione e lo sviluppo di un materiale iniettabile per il riempimento dei difetti ossei. In particolare abbiamo sviluppato un riempitivo composito iniettabile usando materiali biodegradabili di tipo polisaccaridico funzionalizzati con elementi bioattivi come mediatori dell’adesione cellulare, fattori di crescita osteoinduttivi e peptidi di tipo antimicrobico. Il costrutto finale è un composito a due fasi, le cui parti, inizialmente, sono state sviluppate separatamente. La struttura è stata progettata come composta da una parte bioattiva, costituita da microsfere disidratate di alginato e idrossiapatite recanti peptidi, immersa in una matrice veicolante rappresentata da una soluzione concentrata di acido ialuronico. Con lo scopo di ottenere le microsfere bioattive, sono state esplorate diverse tecniche per la coniugazione peptide-polisaccaride e sono stati presi in considerazione svariati sistemi di rilascio di sequenze peptidiche. In particolare sono stati considerati tre peptidi noti per la loro bioattività: peptidi di tipo RGD, sequenza favorente l’adesione cellulare, un frammento della proteina BMP-2 (bone morphogenetic protein-2) in grado di promuovere il differenziamento di cellule mesenchimali ad osteoblasti e LL-37 peptide antimicrobico umano. Per ottenere un costrutto con proprietà bioadesive, gli sforzi sono stati volti ad un miglioramento dell’interfaccia fra le sfere di alginato/idrossiapatite e il tessuto osseo. Questo è stato possibile immobilizzando sulla superficie delle sfere dei peptidi contenti la sequenza RGD e assicurandone il gusto orientamento ed un’alta resa di immobilizzazione. Dopo aver testato diverse strategie chimiche, l’immobilizzazione effettuata sfruttando la formazione di un ponte disolfuro fra ChitLac preventivamente modificato con gruppi tiolici e un peptide contenente un residuo di cisteina, è stata valutata come la miglior strategia in termini di resa di reazione; allo stesso tempo le microsfere funzionalizzate in questo modo hanno dimostrato un’alta capacità di promuovere l’adesione e la crescita di osteoblasti in esperimenti effettuati in vitro. Un altro importante tema ha riguardato l’incorporazione di un frammento della proteina BMP-2 nel costrutto al fine di promuovere il differenziamento e quindi la proliferazione cellulare. La sequenza temporale degli eventi fisiologici, ha suggerito lo sviluppo di un sistema che risulta essere la somma di due diverse strategie di rilascio: la prima caratterizzata dal semplice intrappolamento del peptide in un sistema di sfere di alginato capace di un rilascio veloce, ed il secondo caratterizzato da un rilascio lento e costante ottenuto grazie all’azione idrolitica di esterasi. Questo è stato possibile inserendo un legame enzimaticamente idrolizzabile nella struttura contenente il frammento di BMP. Questa seconda strategia ha sfruttato una chimica altamente selettiva quale la “click chemistry”. La sintesi della molecola spaziatrice recante un legame enzimaticamente idrolizzabile è stata effettuata partendo da un γ-valerolattone. Questo spaziatore è stato inoltre progettato per recare un gruppo terminale funzionale adeguato per le reazioni di click chemistry ed è stato legato al ChitLac. La reazione di cicloaddizone è stata poi effettuata fra il ChitLac funzionalizzato con lo spaziatore e il frammento di BMP anch’esso opportunamente funzionalizzato. L’idrolisi enzimatica è stata verificata, inoltre è stata eseguita un’esaustiva caratterizzazione tramite NMR ed elettroforesi capillare. E’ stata poi presa in considerazione l’incorporazione di peptidi antimicrobici nel costrutto. Partendo da dati di dicroismo circolare riguardanti l’influenza che alcuni polisaccaridi hanno sulla conformazione del peptide LL-37 in soluzione, è stata riconosciuta alla miscela LL- 37/alginato la capacità di modulare la citotossicità del peptide. La miscela ha inoltre dimostrato la capacità di mantenere l’attività antimicrobica su batteri Gram negativi e questo ci ha spinto a considerarne l’applicazione su costrutti solidi con finalità ortopediche. In quest’ambito è stato escluso, da esperimenti in vitro, un effetto causato dal semplice contatto fra cellule o batteri e una superficie di alginato caricato col peptide. L’unico possibile meccanismo di rilascio riscontrato in un costrutto di alginato/LL-37 è stato tramite la degradazione di questo. Infine, il costrutto è stato assemblato incorporando le microsfere disidratate in una soluzione concentrata di acido ialuronico, ottenendo un costrutto dall’aspetto simile ad una pasta che è in grado di facilitare il processo di iniezione del riempitivo. Misure di tipo reologico hanno indicato in incremento della componente viscoelastica aggiungendo il particolato nella soluzione di acido ialuronico, questo generalmente è associato ad una buona capacità di recuperare l’elasticità dopo l’iniezione il che è un requisito richiesto ai biomateriali usati come riempitivi ossei. I risultati ottenuti hanno dimostrato l’applicabilità del composito come sostituto osseo dotato di proprietà bioattivite (osteoconduzione, osteoinduzione, bioadesività ed effetto antimicrobico su ceppi di tipo Gram negativo).
Bone regenerative medicine is considered a potential therapeutic option for the healing of damaged bone tissue. A variety of synthetic bone graft substitutes have been investigated as alternative to current tissue based bone graft materials. In this study efforts have been made to achieve an injectable material to fill bone defects. We have designed composite injectable filler by using polysaccharides as biodegradable materials, and by functionalizing them with bioactive elements such as adhesion mediators, osteoinductive growth factors and anti-microbial peptides. The final construct is represented by a two-phase composite, whose parts have been initially built separately. The structure was thought as composed by bioactive alginate/hydroxyapatite dried microbeads functionalized with peptides, suspended in a concentrate hyaluronic acid solution as the matrix vehicle. With the aim to obtain bioactive alginate/HAp beads, different techniques of peptides-polysaccharides conjugation were considered and different peptide delivery systems were explored. In detail the peptides considered were three, the RGD active sequence with bioadhesive properties, a fragment of BMP-2 (bone morphogenetic protein-2) that promotes the differentiation of MSCs into osteoblasts, and LL-37 a human antimicrobial peptide. In order to obtain a construct with bioadhesive properties, efforts have been made to improve the tissue-alginate/HAp beads interface by immobilizing RGD peptide sequence in a manner that assure the right motif orientation and high yields. After having tested various chemical strategies, the immobilization by disulfide bridge formation between a ChitLac previously modified with a thiol group and a peptide containing a cysteine residue was evaluated to be the best in terms of yield; at the same time μbeads functionalized in that way exhibit a very high osteoblast adhesion and growth promotion in in vitro experiments. Another important topic regarded the incorporation of BMP-2 epitope fragment into the construct, to enhance differentiation and proliferation. Time-tuned physiological functionality suggested the development of a system being the sum of two delivery strategies: the first characterized by simple entrapment in alginate beads for a fast burst release and the second one giving a slow and constant release, obtained by the action of bone esterases on an enzymatically cleavable linker. This second strategy exploited a high selective chemistry such as that of click reactions. Starting by a γ-valerolactone the synthesis of the enzymatically cleavable spacer was performed. The linker was designed to contain a final functional group for click chemistry. It was bound to ChitLac and then to a modified BMP fragment by a click reaction. Enzymatic cleavage was verified and an exhaustively characterization by means of NMR and capillary electrophoresis was performed. The incorporation of antimicrobial peptides was also taken into account. Starting from the information gained by circular dichroism data on the influence on LL-37 conformation given by several polysaccharides, an optimal modulation activity of the cytotoxic effect of LL-37 was found using the peptide/alginate mixture. The demonstrated maintenance of antimicrobial activity on Gram negative strains drove to an application on solid constructs for orthopaedic applications. An effect caused by the simple contact between cells or bacteria and alginate surface loaded with the peptide, was excluded by in vitro experiments. The only possible release mechanism that an LL-37/alginate construct was able to show was related to the degradation of this one. Finally, the whole construct was assembled by incorporating the dried microbeads in a concentrate hyaluronic acid solution, obtaining a paste-like construct that can facilitate the injectability of the particulate. Rheological measurements indicated an increment of the viscoelastic component by adding particulate into hyaluronate solution; this, generally, is associated to a good capacity to regain the elasticity after the injection, as expected for a biomaterial for bone filler applications. The results collected demonstrate the applicability of the obtained composite as bone graft substitute with bioactive properties (osteoinduction, osteoconduction, bioadhesivity and antibiotic effect on Gram negative strains).
XXII Ciclo
1978

博士
國立臺灣大學
醫學工程學研究所
100
While many different filler materials have been applied in vertebral augmentation procedures, none is perfect in all biomechanical and biological characteristics. To minimize possible shortages, we synthesized a new biodegradable, injectable and premixed composite made from poly(propylene fumarate) (PPF) and biphasic α-tricalcium phosphate (α-TCP)/hydroxyapatite (HAP) ceramics powder and evaluated the material properties of the compound in vitro. We mixed the PPF cross-linked by N-Vinyl pyrrolidinone and biphasic α-TCP/HAP powder in different ratios with benzoyl peroxide as an initiator. The setting time and temperature were recorded, although they could be manipulated by differing the concentrations of hydroquinone and N-N-Dimethyl-p-Toluidine. Degradation, cytocompatibility, mechanical properties, and radio-opacity were analyzed after the composites were cured by a cylindrical shape. We also compared the study materials with polymethyl methacrylate (PMMA) and PPF with pure HAP particles. Results showed lower temperature during curing process (38-44oC), sufficient initial mechanical compression fracture strength (61.1±3.7MPa), and gradual degradation were observed in the newly developed bone filler. Radio-opacity in Hounsfield units was similar to PMMA as determined by computed tomography scan. Both pH value variation and cytotoxicity were within biological tolerable limits based on the biocompatibility tests. Mixtures with 70% α-TCP/HAP powder were superior to other groups and were applied in vivo study. To evaluate these cements in vivo, a porcine vertebral model was applied. Besides the before-mentioned 70% α-TCP/HAP/PPF mixture, 70% TtCP/DCP/PPF composite was also recruited in vivo for commercial availability and similar biphasic transformation properties after hydration to compare these two biodegradable cements with PMMA. Twelve miniature pigs had been enrolled in this study. Four cylindrical holes were drilled at the center of lateral cortex of vertebral bodies of lumbar spine with 5mm in diameter and 10mm in length through lateral retroperitoneal approach. The premixed cements were injected into the holes randomly and hardened in situ with setting time and highest setting temperature recorded. After 3months and 6months, the pigs were sacrificed. The retrieved spines specimens were scanned with X-ray and computed tomography. Samples were prepared for histological studies with/without de-calcification. The different appearances of solidified cements and the interaction zones between cement and bone were analyzed and compared. Setting temperatures of PMMA were significantly higher than composite groups. There were two leakages of cement in spinal canals without significant neurological complication. The differences were difficult to be identified by plain X-ray films and CT scans provided better resolutions for morphologic comparisons, volumetric measurement and quantified radiopacity among groups. Little volume, morphology and Hounsfield unit variation of PMMA is detected between 3 months’ and 6 months’ groups and implies inert nature of PMMA cement. Only 2 of 12 PMMA blocks were surrounded by radiolucent lines, and those lines were fibrous tissues in histology. While the remainder without radio-lucent lines were direct bone-PMMA contact. In contrast, irregular sclerotic ring along the cement blocks, significant decreases of cement volume and morphologic changes showed the degradability of both composite cements, despite the decreases of HU were not significant. More cement block laminations, radiolucent halos and vertebral deformities were observed in TtCP/DCP group, and this implied better degradability with obvious influences on surrounding host tissues by released products. Regarding control groups, the defects shrunk significantly with significant increase in Hounsfield units and this indicates good bone healing property of young porcine individuals. New bone formation with substitution of cement were observed in histological specimens of both composite cements groups, but we are unable to quantify the differences between groups for sampling divergences, processing losses, staining errors and observer’s biases. Besides new bone formation and remodeling along outer surfaces of some composites blocks, however in some other blocks, abundant fibrous tissues surrounding, or even invading into blocks, was also observed in some vertebra. Radiological and histological changes were observed in all composite groups and these modifications were along diminished block boundaries. These suggested gradual substitution of decomposed composite by new bone formation, which could not be inspected around PMMA block. In non-decalcified histology, results of PMMA group were more reliable but neither new bone formation nor composite substitution was identified along the PMMA blocks. When combining the results of gross, histological and radiographic finding, each radiologic finding corresponding to a specific histological illustration, such as radio-lucent line indicating histological fibrous tissue and sclerotic rings representing new bone formation with remodeling. Even though it is unable to make histological slices identical completely to CT scan slices, CT scanning could be a preliminary and easy way for evaluation of injectable bone cements in vertebral bodies. This study indicated that these composites of PPF and biphasic CPCs powder are promising, premixed, injectable biodegradable bone fillers for these two composites possessing characteristics better than PMMA’s, but there are still some improvements should be done to increase reliability of the composite in the future.