Smart Hydrogels for the Augmentation of Bone Regeneration by Endogenous Mesenchymal Progenitor Cell Recruitment.

The treatment of bone defects with recombinant bone morphogenetic protein-2 (BMP-2) requires high doses precluding broad clinical application. Here, a bioengineering approach is presented that strongly improves low-dose BMP-2-based bone regeneration by mobilizing healing-associated mesenchymal progenitor cells (MPCs). Smart synthetic hydrogels are used to trap and study endogenous MPCs trafficking to bone defects. Hydrogel-trapped and prospectively isolated MPCs differentiate into multiple lineages in vitro and form bone in vivo. In vitro screenings reveal that platelet-derived growth factor BB (PDGF-BB) strongly recruits prospective MPCs making it a promising candidate for the engineering of hydrogels that enrich endogenous MPCs in vivo. However, PDGF-BB inhibits BMP-2-mediated osteogenesis both in vitro and in vivo. In contrast, smart two-way dynamic release hydrogels with fast-release of PDGF-BB and sustained delivery of BMP-2 beneficially promote the healing of bone defects. Collectively, it is shown that modulating the dynamics of endogenous progenitor cells in vivo by smart synthetic hydrogels significantly improves bone healing and holds great potential for other advanced applications in regenerative medicine.

Sequential Treatment of Metastatic Adenocarcinoma of the Pancreatic Duct with Liver Metastasis Following the NAPOLI-1 Study Protocol with nal-Irinotecan plus 5-FU in the Second Line.

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced or metastatic stage, when curative surgery is not recommended. Therefore, the prognosis is poor for this dismal disease, with only 1-2% of the patients reaching the 5-year survival follow-up. Current advances in systemic treatment with gemcitabine regimens, specifically polychemotherapy with gemcitabine plus nab-paclitaxel or other multidrug regimens such as FOLFIRINOX in the first line, have improved disease control over time. This higher efficacy of systemic treatment enables metastatic PDAC patients to receive second-line treatment more often nowadays. Currently, there is only one regimen for second-line treatment approved by the EMA, FDA, and Swissmedic, based on the phase III NAPOLI-1 study. In this case report, we present an outstanding response to sequential treatment with gemcitabine plus nab-paclitaxel followed by second-line treatment with nal-irinotecan plus 5-fluorouracil.

Expanded skeletal stem and progenitor cells promote and participate in induced bone regeneration at subcritical BMP-2 dose.

The regeneration of large bone defects remains an unsolved clinical problem, which could benefit from recent findings on the biology of skeletal stem and progenitor cells. The elucidation of conditions to specifically control their dynamic and function will likely enable the development of novel treatment strategies. In this study, we aimed at dissecting the role of osteogenic cues and skeletal stem (SSC) and progenitor cell (BCSP) recruitment during biomimetic hydrogel-assisted bone regeneration. To do so, we employed a biomimetic synthetic hydrogel based on poly (ethylene glycol) (PEG), highly controllable and enzymatically crosslinkable. We show that hydrogel-released bone morphogenetic protein-2 (BMP-2) dose-dependently promoted the enrichment of both SSCs and BCSPs within bone defects. Furthermore, we demonstrate that prospectively isolated neonatal bone-derived, as well as expanded SSCs and BCSPs, differentiate into osteogenic cells and enhance the healing of bone defects by low BMP-2 releasing biomaterials. These results indicate that growth factor releasing materials should be designed to first augment the number of SSCs and BCSPs, followed by their osteogenic differentiation to potentiate the healing of bone defects. Additionally, we demonstrate that expanded SSCs and BCSPs are easily accessible cell sources that allow the study of novel bone healing regimen under controlled in vitro and in vivo conditions.

Automatic registration of 2D histological sections to 3D microCT volumes: Trabecular bone.

Histomorphometry and microCT are the two dominant imaging techniques to study bone structure and quality to evaluate repair, regeneration, and disease. These two methods are complementary; where histology provides highly resolved tissue properties on a cellular level in 2D, microCT provides spatial information of bone micro-structure in 3D. For this reason, both of these modalities are commonly used in bone studies. As it is not trivial to combine the images of these two modalities, the two methods are typically applied to different specimens within a study. However, we believe that applying both imaging modalities to the same specimen with a suitable fusion strategy may further strengthen the value of each modality. Therefore, we propose a registration method to align 2D histology slices with a 3D microCT volume, without any prior knowledge of the sectioning direction. In a preprocessing step, bone is extracted from both images. Then, we use a strategy for initializing potential locations, and an iterative approach for searching for an ideal fitting plane using Radon-based rigid transforms and feature-based affine alignments. The algorithm was tested and validated with simulated and real data. For the latter, microCT images of trabecular bone with 76 corresponding histological sections acquired from decalcified and calcified specimens were used. The registration resulted in 94.7% acceptable solutions as defined by a registration orientation error of less than 3°. Average registration accuracy of the acceptable results was 0.6°, leading to a target registration error for our method of 106.3µm, computed based on landmarks annotated by an observer. This corresponds roughly to 10pixels in the images; although, the relation to actual visible structures that provide the features to register, is arguably more relevant.

Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering.

Over the last decades, great strides were made in the development of novel implants for the treatment of bone defects. The increasing versatility and complexity of these implant designs request for concurrent advances in means to assess in vivo the course of induced bone formation in preclinical models. Since its discovery, micro-computed tomography (micro-CT) has excelled as powerful high-resolution technique for non-invasive assessment of newly formed bone tissue. However, micro-CT fails to provide spatiotemporal information on biological processes ongoing during bone regeneration. Conversely, due to the versatile applicability and cost-effectiveness, single photon emission computed tomography (SPECT) would be an ideal technique for assessing such biological processes with high sensitivity and for nuclear imaging comparably high resolution (<1 mm). Herein, we employ modular designed poly(ethylene glycol)-based hydrogels that release bone morphogenetic protein to guide the healing of critical sized calvarial bone defects. By combined in vivo longitudinal multi-pinhole SPECT and micro-CT evaluations we determine the spatiotemporal course of bone formation and remodeling within this synthetic hydrogel implant. End point evaluations by high resolution micro-CT and histological evaluation confirm the value of this approach to follow and optimize bone-inducing biomaterials.

Multicenter evaluation of the fully automated Bactec MGIT 960 system for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide: comparison with the radiometric Bactec 460TB system.

One hundred and fifty clinical isolates of Mycobacterium tuberculosis were tested for susceptibility to pyrazinamide using the fully automated Bactec MGIT 960 system and the radiometric Bactec 460TB system. The overall concordance rate between MGIT 960 and radiometric system was 100% and the mean turnaround times to report the susceptibility test results were almost identical (6.37 and 6.8 days, respectively).