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99mTc-DMSA is one of the most commonly used pediatric nuclear medicine imaging agents. Nevertheless, there are no pharmacokinetic (PK) models for 99mTc-DMSA in children, and currently available pediatric dose estimates for 99mTc-DMSA use pediatric S values with PK data derived from adults. Furthermore, the adult PK data were collected in the mid-70's using quantification techniques and instrumentation available at the time. Using pediatric imaging data for DMSA, we have obtained kinetic parameters for DMSA that differ from those applicable to adults. Methods: We obtained patient data from a retrospective re-evaluation of clinically collected pediatric SPECT images of 99mTc-DMSA in 54 pediatric patients from Boston's Children Hospital (BCH), ranging in age from 1 to 16 years old. These were supplemented by prospective data from twenty-three pediatric patients (age range: 4 months to 6 years old). Results: In pediatric patients, the plateau phase in fractional kidney uptake occurs at a fractional uptake value closer to 0.3 than the value of 0.5 reported by the International Commission on Radiological Protection (ICRP) for adult patients. This leads to a 27% lower time-integrated activity coefficient in pediatric patients than in adults. Over the age range examined, no age dependency in uptake fraction at the clinical imaging time was observed. Female pediatric patients had a 17% higher fractional kidney uptake at the clinical imaging time than males (P < 0.001). Conclusions: Pediatric 99mTc-DMSA kinetics differ from those reported for adults and should be considered in pediatric patient dosimetry. Alternatively, the differences obtained in this study could reflect improved quantification methods and the need to re-examine DMSA kinetics in adults. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have received considerable attention in regenerative medicine, particularly in light of prospects for targeted delivery by intra-arterial injection. However, little is known about the mechanics of MSC sequestration in the microvasculature and the yield pressure (PY), above which MSCs will pass through microvessels of a given diameter. The objectives of the current study were to delineate the dependency of PY on cell size and the heterogeneity of cell mechanical properties and diameters (DCELL) of cultured MSCs. To this end the transient filtration test was employed to elucidate the mean filtration pressure (〈PY〉) for an ensemble of pores of a given size (DPORE) similar to in vivo microvessels. Cultured MSCs had a log-normal distribution of cell diameters (DCELL) with a mean of 15.8 ± 0.73 SD μm. MSC clearance from track-etched polycarbonate filters was studied for pore diameters of 7.3-15.4 μm. The pressure required to clear cells from filters with 30-85 × 103 pores rose exponentially with the ratio λ = DCELL/DPORE for 1.1 ≤ λ ≤ 2.2. The clearance of cells from each filter was characterized by a log-normal distribution in PY, with a mean filtration pressure of 0.02 ≤ 〈PY〉 ≤ 6.7 cmH2O. For λ ≤ 1.56, the yield pressure (PY) was well represented by the cortical shell model of a cell with a viscous interior encapsulated by a shell under cortical tension τ0 = 0.99 ± 0.42 SD dyn/cm. For λ > 1.56, the 〈PY〉 characteristic of the cell population rose exponentially with λ. Analysis of the mean filtration pressure (〈PY〉) of each sample suggested that the larger diameter cells that skewed the distribution of DCELL contributed to about 20% of the mean filtration pressure. Further, if all cells had the same deformability (i.e., PY as a function of λ) as the average cell population, then 〈PY〉 would have risen an order of magnitude above the average from fivefold at λ = 1.56 to 200-fold at λ = 2.1. Comparison of 〈PY〉 to published microvascular pressures suggested that 〈PY〉 may exceed microvessel pressure drops for λ exceeding 2.1, and rise 14-fold above capillary pressure drop at λ = 3 leading to 100% sequestration. However, due to the large variance of in vivo microvascular pressures entrapment of MSCs may be mitigated. Thus it is suggested that selecting fractions of the MSC population according to cell deformability may permit optimization of entrapment at sites targeted for tissue regeneration. [ABSTRACT FROM AUTHOR]

Fibrous scaffolds are used for bone tissue engineering purposes with great success across a variety of polymers with different physical and chemical properties. It is now evident that the correct degree of curvature promotes increased cytoskeletal tension on osteoprogenitors leading to osteogenic differentiation. However, the mechanotransductive pathways involved in this phenomenon are not fully understood. To achieve a reproducible and specific cellular response, an increased mechanistic understanding of the molecular mechanisms driving the fibrous scaffold mediated bone regeneration must be understood. High throughput siRNA mediated screening technology has been utilized for dissecting molecular targets that are important in certain cellular phenotypes. In this study, we used siRNA mediated gene silencing to understand the osteogenic differentiation observed on fibrous scaffolds. A high-throughput siRNA screen was conducted using a library collection of 863 genes including important human kinase and phosphatase targets on pre-osteoblast SaOS-2 cells. The cells were grown on electrospun poly(methyl methacrylate) (PMMA) scaffolds with a diameter of 0.938 ± 0.304 µm and a flat surface control. The osteogenic transcription factor RUNX2 was quantified with an in-cell western (ICW) assay for the primary screen and significant targets were selected via two sample t-test. After selecting the significant targets, a secondary screen was performed to identify osteoinductive markers that also effect cell shape on fibrous topography. Finally, we report the most physiologically relevant molecular signaling mechanisms that are involved in growth factor free, fibrous topography mediated osteoinduction. We identified GTPases, membrane channel proteins, and microtubule associated targets that promote an osteoinductive cell shape on fibrous scaffolds. [ABSTRACT FROM AUTHOR]

This article was updated to correct the spelling of author Brittany L. Banik’s name. [ABSTRACT FROM AUTHOR]