Osseointegration kalthaertender Knochenzemente im Schafmodell

Da es bisher noch kein Knochenersatzmaterial gibt, das den komplexen Eigenschaften des Knochengewebes entspricht, wird intensiv an der Entwicklung neuer Materialien geforscht. In der vorgestellten Studie wurden ein Calciumphosphat- und ein Magnesiumphosphat-Zement (Bruschit bzw. Struvit) in einem unbelasteten und einem teilbelasteten Knochendefekt kritischer Größe im Schafmodell untersucht. Von jeder Zementformulierung kamen zwei unterschiedliche Pulver-Flüssigkeits-Verhältnisse (2,0 und 3,0), welche zu unterschiedlichen Porositäten der abgebundenen Zemente führten, zum Einsatz. Die Implantationszeiträume betrugen 4, 7 und 10 Monate. Als Kontrolle diente bei der 10-Monats-Gruppe ein CDHA-Zement (Ca9(PO4)5HPO4OH) bzw. ein Leerdefekt. Alle Zementformulierungen erwiesen sich als biokompatibel und osteokonduktiv. Bei den Struvit-Zementen (MgNH4PO4•6H2O) konnte nach 10 Monaten Implantation eine fast komplette Degradation beobachtet werden. Diese fand sowohl passiv durch chemisch-physikalische Lösungsvorgänge als auch aktiv, d.h. zellvermittelt, statt. Gleichzeitig bildete sich neues trabekuläres Knochengewebe, so dass gesagt werden kann, dass die Resorptions-geschwindigkeit der Geschwindigkeit der Knochenformation entsprach. Die mechanische Stabilität nahm zwar gegenüber den in vitro ermittelten Werten nach Implantation stark ab, wurde aber im Zeitverlauf durch das Einwachsen von neuem Knochengewebe wieder auf ein physiologisches Niveau angehoben. Signifikante Unterschiede zwischen den Porositäten gab es nur zum Teil hinsichtlich des verbliebenen Zementvolumens. Aufgrund der besseren Verarbeitbarkeit als injizierbare Paste, wäre ein Pulver-Flüssigkeits-Verhältnis von 2,0 eventuell besser für den klinischen Einsatz geeignet als ein Pulver-Flüssigkeits-Verhältnis von 3,0. In Kontakt mit Weichgewebe lösten sich die Struvit-Zemente schneller auf als neues Knochengewebe einwachsen konnte. Durch weitere Modifikationen bei der Zementzusammensetzung könnte dies verhindert werden. Durch die Kombination mit einem im Verhältnis zu Struvit stabileren Calciumphosphat (z.B. β-Tricalciumphosphat) könnte ein biphasischer Zement entwickelt werden, bei dem sich die einzelnen Komponenten unterschiedlich schnell auflösen. Die Bruschit-Zemente (CaHPO4•2H2O) und der CDHA-Zement zeigten selbst nach zehn Monaten Implantation kaum Degradation. Bei dem CDHA-Zement war dies zu erwarten, bei den Bruschit-Zementen jedoch nicht. Die Ursache hierfür kann bei der höheren Porosität (PLR 2,0) in der Phasenumwandlung von Bruschit zu Octacalciumphosphat bzw. generell in der Zementkomposition gesehen werden. Da die Bruschit-Zemente im teilbelasteten Defekt Risse aufwiesen, war ihre mechanische Stabilität in vivo für lasttragende Bereiche nicht ausreichend. Deshalb wäre es nötig, die Bruschit-Zemente weiter zu modifizieren, bevor sie erneut im Tiermodell untersucht werden können. Um die Stabilität zu verbessern, könnten Keramik- oder Polymerfasern in den Zement eingebracht werden. Für die Verbesserung der Degradation sollte eine andere Flüssigkeitskomponente, z. B. Natriumhyaluronat oder Pyrophosphat, wie sie in anderen Studien verwendet wurden, in Betracht gezogen werden. Zusätzlich zu den orthotopen Implantaten wurden jeweils auch subkutan Formkörper eingebracht. Diese zeigten, dass die untersuchten Zemente auch eine gewisse Osseoinduktivität besaßen. Im Fall der Bruschit-Zemente verhielten sich die subkutanen Implantate allerdings anders als die im Knochen implantierten Zemente. Im Gegensatz zu den orthotopen Implantaten zeigten die Formkörper im subkutanen Gewebe eingesetzt eine deutliche Größenreduktion. Die Ursache dafür kann im unterschiedlichen Gewebemilieu oder in der unterschiedlichen Implantatform (orthotop: Paste / heterotop: Block) gesehen werden. Um eine möglichst genaue Aussage über das biologische Verhalten eines Materials treffen zu können, ist es daher notwendig, die Materialien immer in der Form und im entsprechenden Zielgewebe zu untersuchen, wie sie später verwendet werden sollen, d.h. ein Zement als resorbierbares Knochenersatzmaterial sollte immer als Paste im Knochenlager untersucht werden. Auch eine Untersuchung in einem belasteten Implantationsmodell ist sinnvoll, da eine mechanische Belastung einen Einfluss auf das Verhalten der Zemente und das Knochenremodelling hat.Osseointegration of cold-setting bone-cements in an ovine model The perfect bone substitute material which matches the properties of bone has still not been found. Therefore, intensive research is on-going. In the present study a calciumphosphate- and a magnesiumphosphate-cement (brushite and struvite respectively) were investigated. The cements were implanted in sheep using a partially loaded and an unloaded critical size bone defect. Each formulation was tested in two different powder-to-liquid-ratios (PLR 2.0 and 3.0), resulting in different porosities of the hardened cements. The implantation periods were 4, 7 and 10 months. For the 10 months’ group there were two controls: a CDHA cement (Ca9(PO4)5HPO4OH) and an unfilled defect. Every investigated cement formulation proved to be biocompatible and osteoconductive. After ten months of implantation in live sheep, the struvite cements (MgNH4PO4•6H2O) showed a nearly complete degradation which was closely followed by new trabecular bone formation. The degradation observed was both passive to chemical dissolution and active to cellular activity. The mechanical properties of the struvite-cements decreased extensively, up to 90 %, after implantation. However, over the ten months of this study, the stiffness level caused by the infilling bone reached normal physiological ranges. There were no significant differences between the porosities except in the area of residual cement in some cases. Nevertheless, for clinical use, a PLR of 2.0 would be preferable to a PLR of 3.0 because an injectable cement provides better handling. When the struvite cement is in contact with soft tissue, it dissolves too quickly for proper bone ingrowth. Therefore, further modifications to the cement formulation are required. For example, a biphasic cement could be developed in which the individual components dissolve at different rates. This could be achieved through the combination of struvite and a more stable calcium phosphate (eg, β-tricalcium phosphate). The brushite cements (CaHPO4•2H2O), as well as the CDHA cement, showed barely any resorption even after ten months of implantation. For the CDHA cement this was expected, but not for the brushite cements. These findings could be due to changes in the phase composition which occured in the brushite cements with a PLR of 2.0, rather than due to the cement formulation itself. The partially-loaded defect model revealed that the brushite cements were not suitable for load-bearing applications because cracks formed in the cement. Hence, it is recommended that the cement formulations be modified before they are investigated again. To enhance the stability, ceramic or polymer fibers might prove successful when incorporated into the cement. To improve degradation behavior, another liquid component such as sodiumhyaluronat or pyrophosphate, as used in other studies, should be considered. In addition to the bone implants, moulds of each cement formulation were implanted subcutaneousely. Bone formation at these implants exhibited certain osteoinductive properties of the cements. By the time of implantation, the subcutaneous brushite implants had reduced in volume in contrast to the bone implants. The cause may be found in the different tissue milieu or in the different implant type (orthotopic: paste / heterotopic: block). When researching the specific biological behaviours of a biomaterial, it is necessary to examine the materials using them with the same type and corresponding target tissue as it will be used in clinical use. In such cases, cements used as resorbable bone substitute materials should always be investigated as a paste and in a suitable bone defect. Also, a study in a loaded implant model is useful, since a mechanical load has an influence on the behavior of the cements and the bone remodelling

In vivo biofunctional evaluation of hydrogels for disc regeneration

Purpose Regenerative strategies aim to restore the original biofunctionality of the intervertebral disc. Different biomaterials are available, which might support disc regeneration. In the present study, the prospects of success of two hydrogels functionalized with anti-angiogenic peptides and seeded with bone marrow derived mononuclear cells (BMC), respectively, were investigated in an ovine nucleotomy model. Methods In a one-step procedure iliac crest aspirates were harvested and, subsequently, separated BMC were seeded on hydrogels and implanted into the ovine disc. For the cell-seeded approach a hyaluronic acid-based hydrogel was used. The anti-angiogenic potential of newly developed VEGF-blockers was investigated on ionically crosslinked metacrylated gellan gum hydrogels. Untreated discs served as nucleotomy controls. 24 adult merino sheep were used. After 6 weeks histological, after 12 weeks histological and biomechanical analyses were conducted. Results Biomechanical tests revealed no differences between any of the implanted and nucleotomized discs. All implanted discs significantly degenerated compared to intact discs. In contrast, there was no marked difference between implanted and nucleotomized discs. In tendency, albeit not significant, degeneration score and disc height index deteriorated for all but not for the cell-seeded hydrogels from 6 to 12 weeks. Cell-seeded hydrogels slightly decelerated degeneration. Conclusions None of the hydrogel configurations was able to regenerate biofunctionality of the intervertebral disc. This might presumably be caused by hydrogel extrusion. Great importance should be given to the development of annulus sealants, which effectively exploit the potential of (cell-seeded) hydrogels for biological disc regeneration and restoration of intervertebral disc functioningThis work was supported by the EU-project Disc Regeneration (NMP3-LA-2008-213904). Technical assistance of Iris Baum and the whole animal surgery team of the Institute of Orthopaedic Research and Biomechanics, Ulm, are gratefully acknowledged. DDAHA hydrogels were kindly provided by Cristina Longinotti (DDAHA, Anika Therapeutics, Abano Therme, Italy)

Neuroworsening in the Emergency Department Is a Predictor of Traumatic Brain Injury Intervention and Outcome: A TRACK-TBI Pilot Study.

IntroductionNeuroworsening may be a sign of progressive brain injury and is a factor for treatment of traumatic brain injury (TBI) in intensive care settings. The implications of neuroworsening for clinical management and long-term sequelae of TBI in the emergency department (ED) require characterization.MethodsAdult TBI subjects from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study with ED admission and disposition Glasgow Coma Scale (GCS) scores were extracted. All patients received head computed tomography (CT) scan <24 h post-injury. Neuroworsening was defined as a decline in motor GCS at ED disposition (vs. ED admission). Clinical and CT characteristics, neurosurgical intervention, in-hospital mortality, and 3- and 6-month Glasgow Outcome Scale-Extended (GOS-E) scores were compared by neuroworsening status. Multivariable regressions were performed for neurosurgical intervention and unfavorable outcome (GOS-E ≤ 3). Multivariable odds ratios (mOR) with [95% confidence intervals] were reported.ResultsIn 481 subjects, 91.1% had ED admission GCS 13-15 and 3.3% had neuroworsening. All neuroworsening subjects were admitted to intensive care unit (vs. non-neuroworsening: 26.2%) and were CT-positive for structural injury (vs. 45.4%). Neuroworsening was associated with subdural (75.0%/22.2%), subarachnoid (81.3%/31.2%), and intraventricular hemorrhage (18.8%/2.2%), contusion (68.8%/20.4%), midline shift (50.0%/2.6%), cisternal compression (56.3%/5.6%), and cerebral edema (68.8%/12.3%; all p < 0.001). Neuroworsening subjects had higher likelihoods of cranial surgery (56.3%/3.5%), intracranial pressure (ICP) monitoring (62.5%/2.6%), in-hospital mortality (37.5%/0.6%), and unfavorable 3- and 6-month outcome (58.3%/4.9%; 53.8%/6.2%; all p < 0.001). On multivariable analysis, neuroworsening predicted surgery (mOR = 4.65 [1.02-21.19]), ICP monitoring (mOR = 15.48 [2.92-81.85], and unfavorable 3- and 6-month outcome (mOR = 5.36 [1.13-25.36]; mOR = 5.68 [1.18-27.35]).ConclusionsNeuroworsening in the ED is an early indicator of TBI severity, and a predictor of neurosurgical intervention and unfavorable outcome. Clinicians must be vigilant in detecting neuroworsening, as affected patients are at increased risk for poor outcomes and may benefit from immediate therapeutic interventions

Neuroworsening in the Emergency Department Is a Predictor of Traumatic Brain Injury Intervention and Outcome: A TRACK-TBI Pilot Study.

INTRODUCTION: Neuroworsening may be a sign of progressive brain injury and is a factor for treatment of traumatic brain injury (TBI) in intensive care settings. The implications of neuroworsening for clinical management and long-term sequelae of TBI in the emergency department (ED) require characterization. METHODS: Adult TBI subjects from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study with ED admission and disposition Glasgow Coma Scale (GCS) scores were extracted. All patients received head computed tomography (CT) scan(vs. ED admission). Clinical and CT characteristics, neurosurgical intervention, in-hospital mortality, and 3- and 6-month Glasgow Outcome Scale-Extended (GOS-E) scores were compared by neuroworsening status. Multivariable regressions were performed for neurosurgical intervention and unfavorable outcome (GOS-E ≤ 3). Multivariable odds ratios (mOR) with [95% confidence intervals] were reported. RESULTS: In 481 subjects, 91.1% had ED admission GCS 13-15 and 3.3% had neuroworsening. All neuroworsening subjects were admitted to intensive care unit (vs. non-neuroworsening: 26.2%) and were CT-positive for structural injury (vs. 45.4%). Neuroworsening was associated with subdural (75.0%/22.2%), subarachnoid (81.3%/31.2%), and intraventricular hemorrhage (18.8%/2.2%), contusion (68.8%/20.4%), midline shift (50.0%/2.6%), cisternal compression (56.3%/5.6%), and cerebral edema (68.8%/12.3%; all CONCLUSIONS: Neuroworsening in the ED is an early indicator of TBI severity, and a predictor of neurosurgical intervention and unfavorable outcome. Clinicians must be vigilant in detecting neuroworsening, as affected patients are at increased risk for poor outcomes and may benefit from immediate therapeutic interventions