Optimization of Aging Temperature and Heat-Treatment Pathways in Additively Manufactured 17-4PH Stainless Steel.

This study investigates the tensile behaviors of additively manufactured (AM) 17-4PH stainless steels heat-treated within various temperature ranges from 400 °C to 700 °C in order to identify the effective aging temperature. Despite an aging treatment of 400-460 °C increasing the retained austenite content, an enhancement of the tensile properties was achieved without a strength-ductility trade-off owing to precipitation hardening by the Cu particles. Due to the intricate evolution of the microstructure, aging treatments above 490 °C led to a loss in yield strength and ductility. A considerable rise in strength and a decrease in ductility were brought about by the increase in the fraction of precipitation-hardened martensitic matrix in aging treatments over 640 °C. The impact of heat-treatment pathways on aging effectiveness and tensile anisotropy was then examined. Direct aging at 482 °C for an hour had hardly any effect on wrought 17-4PH, but it increased the yield strength of AM counterparts from 436-457 to 588-604 MPa. A solid-solution treatment at 1038 °C for one hour resulted in a significant drop in the austenite fraction, which led to an increase in the yield (from 436-457 to 841-919 MPa) and tensile strengths (from 1106-1127 to 1254-1256 MPa) with a sacrifice in ductility. Improved strength and ductility were realized by a solid-solution followed by an aging treatment, achieving 1371-1399 MPa. The tensile behaviors of AM 17-4PH were isotropic both parallel and perpendicular to the building direction.

Transient Phase-Driven Cyclic Deformation in Additively Manufactured 15-5 PH Steel.

The present work extends the examination of selective laser melting (SLM)-fabricated 15-5 PH steel with the 8%-transient-austenite-phase towards fully-reversed strain-controlled low-cycle fatigue (LCF) test. The cyclic-deformation response and microstructural evolution were investigated via in-situ neutron-diffraction measurements. The transient-austenite-phase rapidly transformed into the martensite phase in the initial cyclic-hardening stage, followed by an almost complete martensitic transformation in the cyclic-softening and steady stage. The compressive stress was much greater than the tensile stress at the same strain amplitude. The enhanced martensitic transformation associated with lower dislocation densities under compression predominantly governed such a striking tension-compression asymmetry in the SLM-built 15-5 PH.

Tailoring grain sizes of the biodegradable iron-based alloys by pre-additive manufacturing microalloying.

We demonstrated the design of pre-additive manufacturing microalloying elements in tuning the microstructure of iron (Fe)-based alloys for their tunable mechanical properties. We tailored the microalloying stoichiometry of the feedstock to control the grain sizes of the metallic alloy systems. Two specific microalloying stoichiometries were reported, namely biodegradable iron powder with 99.5% purity (BDFe) and that with 98.5% (BDFe-Mo). Compared with the BDFe, the BDFe-Mo powder was found to have lower coefficient of thermal expansion (CTE) value and better oxidation resistance during consecutive heating and cooling cycles. The selective laser melting (SLM)-built BDFe-Mo exhibited high ultimate tensile strength (UTS) of 1200 MPa and fair elongation of 13.5%, while the SLM-built BDFe alloy revealed a much lower UTS of 495 MPa and a relatively better elongation of 17.5%, indicating the strength enhancement compared with the other biodegradable systems. Such an enhanced mechanical behavior in the BDFe-Mo was assigned to the dominant mechanism of ferrite grain refinement coupled with precipitate strengthening. Our findings suggest the tunability of outstanding strength-ductility combination by tailoring the pre-additive manufacturing microalloying elements with their proper concentrations.

Unravelling thermal history during additive manufacturing of martensitic stainless steel.

In-situ thermal cycling neutron diffraction experiments were employed to unravel the effect of thermal history on the evolution of phase stability and internal stresses during the additive manufacturing (AM) process. While the fully-reversible martensite-austenite phase transformation was observed in the earlier thermal cycles where heating temperatures were higher than Af, the subsequent damped thermal cycles exhibited irreversible phase transformation forming reverted austenite. With increasing number of thermal cycles, the thermal stability of the retained austenite increased, which decreased the coefficient of thermal expansion. However, martensite revealed higher compressive residual stresses and lower dislocation density, indicating inhomogeneous distributions of the residual stresses and microstructures on the inside and on the surface of the AM component. The compressive residual stresses that acted on the martensite resulted preferentially from transformation strain and additionally from thermal misfit strain, and the decrease in the dislocation density might have been due to the strong recovery effect near the Ac1 temperature.

Dual-modal cancer detection based on optical pH sensing and Raman spectroscopy.

A dual-modal approach using Raman spectroscopy and optical pH sensing was investigated to discriminate between normal and cancerous tissues. Raman spectroscopy has demonstrated the potential for in vivo cancer detection. However, Raman spectroscopy has suffered from strong fluorescence background of biological samples and subtle spectral differences between normal and disease tissues. To overcome those issues, pH sensing is adopted to Raman spectroscopy as a dual-modal approach. Based on the fact that the pH level in cancerous tissues is lower than that in normal tissues due to insufficient vasculature formation, the dual-modal approach combining the chemical information of Raman spectrum and the metabolic information of pH level can improve the specificity of cancer diagnosis. From human breast tissue samples, Raman spectra and pH levels are measured using fiber-optic-based Raman and pH probes, respectively. The pH sensing is based on the dependence of pH level on optical transmission spectrum. Multivariate statistical analysis is performed to evaluate the classification capability of the dual-modal method. The analytical results show that the dual-modal method based on Raman spectroscopy and optical pH sensing can improve the performance of cancer classification.

Nanoparticle-mediated radiofrequency capacitive hyperthermia: A phantom study with magnetic resonance thermometry.

In hyperthermia, focusing heat generation on tumour tissues and precisely monitoring the temperature around the tumour region is important. To focus heat generation in radiofrequency (RF) capacitive heating, magnetic nanoparticles suspended in sodium carboxymethyl cellulose (CMC) solution were used, based on the hypothesis that the nanoparticle suspension would elevate electrical conductivity and RF current density at the nanoparticle-populated region. A tissue-mimicking phantom with compartments with and without nanoparticles was made for RF capacitive heating experiments. An FDTD model of the phantom was developed to simulate temperature increases at the phantom. To monitor temperature inside the phantom, MR thermometry was performed intermittently during RF heating inside a 3Tesla MRI magnet bore. FDTD simulation on the phantom model was performed in two steps: electromagnetic simulation to compute specific absorption rate and thermal simulation to compute temperature changes. Experimental temperature maps were similar to simulated temperature maps, demonstrating that nanoparticle-populated regions drew more heat than background regions. Nanoparticle-mediated RF heating could mitigate concerns about normal tissue death during RF capacitive hyperthermia.

Time-multiplexed two-channel capacitive radiofrequency hyperthermia with nanoparticle mediation.

BACKGROUND: Capacitive radiofrequency (RF) hyperthermia suffers from excessive temperature rise near the electrodes and poorly localized heat transfer to the deep-seated tumor region even though it is known to have potential to cure ill-conditioned tumors. To better localize heat transfer to the deep-seated target region in which electrical conductivity is elevated by nanoparticle mediation, two-channel capacitive RF heating has been tried on a phantom. METHODS: We made a tissue-mimicking phantom consisting of two compartments, a tumor-tissue-mimicking insert against uniform background agarose. The tumor-tissue-mimicking insert was made to have higher electrical conductivity than the normal-tissue-mimicking background by applying magnetic nanoparticle suspension to the insert. Two electrode pairs were attached on the phantom surface by equal-angle separation to apply RF electric field to the phantom. To better localize heat transfer to the tumor-tissue-mimicking insert, RF power with a frequency of 26 MHz was delivered to the two channels in a time-multiplexed way. To monitor the temperature rise inside the phantom, MR thermometry was performed at a 3T MRI intermittently during the RF heating. Finite-difference-time-domain (FDTD) electromagnetic and thermal simulations on the phantom model were also performed to verify the experimental results. RESULTS: As compared to the one-channel RF heating, the two-channel RF heating with time-multiplexed driving improved the spatial localization of heat transfer to the tumor-tissue-mimicking region in both the simulation and experiment. The two-channel RF heating also reduced the temperature rise near the electrodes significantly. CONCLUSIONS: Time-multiplexed two-channel capacitive RF heating has the capability to better localize heat transfer to the nanoparticle-mediated tumor region which has higher electrical conductivity than the background normal tissues.

Iterative multi-channel radio frequency pulse calibration with improving B1 field uniformity in high field MRI.

BACKGROUND: In high field MRI capable of multi-channel radio frequency (RF) transmission, B 1 shimming is a time-consuming job because conventional B 1 shimming techniques require B 1 mapping for each channel. After acquiring the complex-numbered B 1 field maps, the optimal amplitude and phase of the driving RF pulse are determined for each channel to maximize the B 1 field uniformity in conventional B 1 shimming. However, time-consuming B 1 shimming procedures at the pre-scan may not be tolerated in the clinical imaging in which patient throughput is one of the important factors. METHODS: To avoid the time-consuming B 1 mapping, the first spin echo and the stimulated echo were repeatedly acquired in the slice-selective stimulated echo sequence without imaging gradients. A cost function of the amplitudes and phases of the driving RF pulse for every channel was defined in a way that the ratio between the spin echo and stimulated echo amplitudes rapidly converged to √ 2. The amplitude and phase of the driving RF pulse were iteratively modified over the repeating RF pulse sequence so that the cost function was minimized. RESULTS: From the finite-difference-time-domain (FDTD) electromagnetic field simulations with a human body model placed in a birdcage coil operating at 3 T, it was observed that the RF pulse calibration with iterative cost function minimization can give improvement of B1 field uniformity as well as flip-angle calibration. The experiments at 3 T also showed improvement of RF field uniformity in the phantom imaging studies. CONCLUSIONS: Since the proposed RF pulse calibration is not based on B 1 mapping, the RF pulse calibration time could be much shorter than the B 1-mapping based methods. The proposed method is expected to be a practical substitute for the B 1-mapping-based B 1 shimming methods when long pre-scan time is not tolerable.

Lesion edge preserved direct average strain estimation for ultrasound elasticity imaging.

Elasticity imaging techniques with built-in or regularization-based smoothing feature for ensuring strain continuity are not intelligent enough to prevent distortion or lesion edge blurring while smoothing. This paper proposes a novel approach with built-in lesion edge preservation technique for high quality direct average strain imaging. An edge detection scheme, typically used in diffusion filtering is modified here for lesion edge detection. Based on the extracted edge information, lesion edges are preserved by modifying the strain determining cost function in the direct-average-strain-estimation (DASE) method. The proposed algorithm demonstrates approximately 3.42-4.25 dB improvement in terms of edge-mean-square-error (EMSE) than the other reported regularized or average strain estimation techniques in finite-element-modeling (FEM) simulation with almost no sacrifice in elastographic-signal-to-noise-ratio (SNRe) and elastographic-contrast-to-noise-ratio (CNRe) metrics. The efficacy of the proposed algorithm is also tested for the experimental phantom data and in vivo breast data. The results reveal that the proposed method can generate a high quality strain image delineating the lesion edge more clearly than the other reported strain estimation techniques that have been designed to ensure strain continuity. The computational cost, however, is little higher for the proposed method than the simpler DASE and considerably higher than that of the 2D analytic minimization (AM2D) method.

Phase-based direct average strain estimation for elastography.

In this paper, a phase-based direct average strain estimation method is developed. A mathematical model is presented to calculate axial strain directly from the phase of the zero-lag cross-correlation function between the windowed precompression and stretched post-compression analytic signals. Unlike phase-based conventional strain estimators, for which strain is computed from the displacement field, strain in this paper is computed in one step using the secant algorithm by exploiting the direct phase-strain relationship. To maintain strain continuity, instead of using the instantaneous phase of the interrogative window alone, an average phase function is defined using the phases of the neighboring windows with the assumption that the strain is essentially similar in a close physical proximity to the interrogative window. This method accounts for the effect of lateral shift but without requiring a prior estimate of the applied strain. Moreover, the strain can be computed both in the compression and relaxation phases of the applied pressure. The performance of the proposed strain estimator is analyzed in terms of the quality metrics elastographic signal-to-noise ratio (SNRe), elastographic contrast-to-noise ratio (CNRe), and mean structural similarity (MSSIM), using a finite element modeling simulation phantom. The results reveal that the proposed method performs satisfactorily in terms of all the three indices for up to 2.5% applied strain. Comparative results using simulation and experimental phantom data, and in vivo breast data of benign and malignant masses also demonstrate that the strain image quality of our method is better than the other reported techniques.

Using nearest neighbors for accurate estimation of ultrasonic attenuation in the spectral domain.

Attenuation is a key diagnostic parameter of tissue pathology change and thus may play a vital role in the quantitative discrimination of malignant and benign tumors in soft tissue. In this paper, two novel techniques are proposed for estimating the average ultrasonic attenuation in soft tissue using the spectral domain weighted nearest neighbor method. Because the attenuation coefficient of soft tissues can be considered to be a continuous function in a small neighborhood, we directly estimate an average value of it from the slope of the regression line fitted to the 1) modified average midband fit value and 2) the average center frequency shift along the depth. To calculate the average midband fit value, an average regression line computed from the exponentially weighted short-time Fourier transform (STFT) of the neighboring 1-D signal blocks, in the axial and lateral directions, is fitted over the usable bandwidth of the normalized power spectrum. The average center frequency downshift is computed from the maximization of a cost function defined from the normalized spectral cross-correlation (NSCC) of exponentially weighted nearest neighbors in both directions. Different from the large spatial signal-block-based spectral stability approach, a costfunction- based approach incorporating NSCC functions of neighboring 1-D signal blocks is introduced. This paves the way for using comparatively smaller spatial area along the lateral direction, a necessity for producing more realistic attenuation estimates for heterogeneous tissue. For accurate estimation of the attenuation coefficient, we also adopt a reference-phantombased diffraction-correction technique for both methods. The proposed attenuation estimation algorithm demonstrates better performance than other reported techniques in the tissue-mimicking phantom and the in vivo breast data analysis.

Direct and gradient-based average strain estimation by using weighted nearest neighbor cross-correlation peaks.

In this paper, two novel approaches, gradient-based and direct strain estimation techniques, are proposed for high-quality average strain imaging incorporating a cost function maximization. Stiffness typically is a continuous function. Consequently, stiffness of proximal tissues is very close to that of the tissue corresponding to a given data window. Hence, a cost function is defined from exponentially weighted neighboring pre- and post-compression RF echo normalized cross-correlation peaks in the lateral (for displacement estimation) or in both the axial and the lateral (for direct strain estimation) directions. This enforces a controlled continuity in displacement/strain and average displacement/strain is calculated from the corresponding maximized cost function. Axial stress causes lateral shift in the tissue. Therefore, a 1-D post-compression echo segment is selected by incorporating Poisson's ratio. Two stretching factors are considered simultaneously in gradient-based strain estimation that allow imaging the lesions properly. The proposed time-domain gradient-based and direct-strain-estimation-based algorithms demonstrate significantly better performance in terms of elastographic signal-to-noise ratio (SNRe), elastographic contrast-to-noise ratio (CNRe), peak signal-to-noise ratio (PSNR), and mean structural similarity (MSSIM) than the other reported time-domain gradient-based and direct-strain-estimation techniques in finite element modeling (FEM) simulation and phantom experiments. For example, in FEM simulation, it has been found that the proposed direct strain estimation method can improve up to approximately 2.49 to 8.71, 2.2 to 6.63, 1.5 to 5, and 1.59 to 2.45 dB in the SNRe, CNRe, PSNR, and MSSIM compared with the traditional direct strain estimation method, respectively, and the proposed gradient-based algorithm demonstrates 2.99 to 16.26, 18.74 to 23.88, 3 to 9.5, and 0.6 to 5.36 dB improvement in the SNRe, CNRe, PSNR, and MSSIM, respectively, compared with a recently reported time-domain gradient-based technique. The range of improvement as noted above is for low to high applied strains. In addition, the comparative results using the in vivo breast data (including malignant or benign masses) also show that the lesion size is better defined by the proposed gradient-based average strain estimation technique.

Direct mean strain estimation for elastography using nearest-neighbor weighted least-squares approach in the frequency domain.

Ultrasound elastography is emerging with enormous potential as a medical imaging modality for effective discrimination of pathological changes in soft tissue. It maps the tissue elasticity or strain due to a mechanical deformation applied to it. The strain image most often calculated from the derivative of the local displacement field is highly noisy because of the de-correlation effect mainly due to unstable free-hand scanning and/or irregular tissue motion; consequently, improving the SNR of the strain image is still a challenging problem in this area. In this paper, a novel approach using the nearest-neighbor weighted least-squares is presented for direct estimation of the 'mean' axial strain for high quality strain imaging. Like other time/frequency domain reported schemes, the proposed method exploits the fact that the post-compression rf echo signal is a time-scaled and shifted replica of the pre-compression rf echo signal. However, the elegance of our technique is that it directly computes the mean strain without explicitly using any post filter and/or previous local displacement/strain estimates as is usually done in the conventional approaches. It is implemented in the short-time Fourier transform domain through a nearest-neighbor weighted least-squares-based Fourier spectrum equalization technique. As the local tissue strain is expected to maintain continuity with its neighbors, we show here that the mean strain at the interrogative window can be directly computed from the common stretching factor that minimizes a cost function derived from the exponentially weighted windowed pre- and post-compression rf echo segments in both the lateral and axial directions. The performance of our algorithm is verified for up to 8% applied strain using simulation and experimental phantom data and the results reveal that the SNR of the strain image can be significantly improved compared to other reported algorithms in the literature. The efficacy of the algorithm is also tested with in vivo breast data known to have malignant or benign masses from histology.

Tracheal replacement with fresh and cryopreserved aortic allograft in adult dog.

BACKGROUND: Many reports have described tracheal replacement using aortic allografts, with varying results and minimal understanding of the mechanism of tracheal regeneration. The present study attempted tracheal regeneration in adult dogs using fresh aortic allografts (FAA) and cryopreserved aortic allografts (CAA). MATERIALS AND METHODS: Twelve adult beagles underwent tracheal resection and were transplanted with FAA (n = 5) or CAA (n = 7). Animals were followed-up with serial radiography and magnetic resonance imaging, and were euthanized at predetermined times up to 16 mo post-surgery. RESULTS: There were no procedural deaths, but two animals died due to stent migration. Stent migration occurred in seven of the 12 animals. Evidence of regeneration of tracheal epithelium was observed in the surviving animals, with the transformation of squamous metaplasia to mucociliary epithelium being time-dependent. Islet of cartilage were observed in animals after 6 mo, but ring-like cartilage structures were absent, even after 16 mo. During autopsy, axial graft contractions up to 68% were observed. Serial radiographs show that most of the contraction occurred within 1 mo. The results of the MRI showed that the graft area was strongly enhanced for up to 2 mo, but was clearly reduced after 3 mo. CONCLUSIONS: Tracheal replacement in adult dogs using FAA or CAA is feasible. However, immaturity of the neotracheal cartilage did not allow the tissue to function as native tracheal tissue. Prolonged stenting should be considered in adult if the procedure is to be clinically contemplated.

Strain measurement from 3D micro-CT images of a breast-mimicking phantom.

Strain distribution in compressed tissues gives information about elasticity of the tissues. We have measured strain from two sets of 3D micro-CT images of a breast-mimicking phantom; one obtained without compressing the phantom and the other with compressing it. To measure strain, we first calculated compression-induced displacements of high-intensity feature patterns in the image. In measuring displacement of a pixel of interest, we searched the pixel in the compressed-phantom image, whose surrounding resembles the uncompressed-phantom image most closely, using the image correlation technique. From the displacement data, we calculated average strain at a region of interest. With the calculated average strains, we could distinguish the hard inclusion in the phantom which was not distinguishable from the background body of the phantom in the ordinary micro-CT images. The calculated strains account for stiffness of the tissue of interest, one of the important parameters for diagnosing malignant tissues. We present experimental results of the displacement and strain measurement along with FEM analysis results.

Removal of ring artifacts in CT imaging through detection and correction of stripes in the sinogram.

Due to malfunctioning and mis-calibration of cells in digital x-ray detectors as well as impurities on the scintillator screens, stripe artifacts arise in the sinogram which in turn generate ring artifacts in the reconstructed x-ray computed tomography images. In this paper, a novel technique is proposed for the detection and removal of stripe artifacts in a sinogram with a view to suppress the ring artifacts from the tomographic images. To accurately detect the stripe creating pixels using a derivative-based algorithm, at first the sinogram is windowed to create a sub-sinogram by keeping the pixel of examination at the center position in the sub-sinogram. The other pixels in the sub-sinogram are selected from a polyphase component of the sinogram. A new mathematical index is proposed here to isolate the strong and weak ring-generating stripes from the good ones. For the correction of strong ring artifacts resulting from the defective detector elements and dusty scintillator crystals, 2D variable window moving average and weighted moving average filters are proposed in this work. On the other hand, a conventionally trusted constant bias correction scheme is adopted to correct the responses of the mis-calibrated detector elements. To evaluate and compare the performance of the proposed algorithm, real micro-CT images acquired from two flat panel detectors under different operating conditions are used. Experimental results show that the proposed method can remove ring artifacts more effectively without imparting noticeable distortion in the image as compared to a recently reported technique in the literature.

Finite element simulation of ultrasound propagation in bone for quantitative ultrasound toward the diagnosis of osteoporosis.

Osteoporosis is a serious bone disease which leads to the increased risk of bone fractures. For prevention and therapy, early detection of osteoporosis is critical. In general, for diagnosis of osteoporosis, dual-energy X-ray absoptiometry (DXA) or densitometry is most commonly used. However DXA exhibits some disadvantages such as ionizing radiation, relatively expensive cost, and limited information on mineralization and geometry of the bone. As an alternative method of DXA, quantitative ultrasound (QUS) is being investigated. In contrast to DXA, QUS is non-ionizing and relatively inexpensive. It can also provide some bone-related parameters (e.g., quantitative measurements including speed of sound and frequency-dependent attenuation). However the estimation of these parameters is difficult and few analytical solutions exist due to the complex behavior of ultrasound propagation in bone. As an alternative to the analytical methods, in most attempts, finite difference time domain (FDTD) method is used for simulation of ultrasound propagation in bone with a limited capability of modeling complex geometries of the bone. Finite element method (FEM) is a better solution since it can handle the complex geometry, but has been rarely applied due to its computational complexity. In this work, we propose an approach of FEM-based simulation of ultrasound propagation in bone. To validate our approach, we have tested simulated and real bone models from micro-CT using the index of speed-of-sound. Our results achieve an average of 97.54% in the computational accuracy.

Intraarterially delivered human umbilical cord blood-derived mesenchymal stem cells in canine cerebral ischemia.

The present study examined the effects of human umbilical cord blood-derived mesenchymal stem cells (HUCB-derived MSCs) delivered through the basilar artery in a canine thromboembolic brain ischemia model. Cerebral ischemia was induced through occlusion of the middle cerebral artery by injecting thrombus emboli into 10 beagles. In the HUCBC group (n = 5), 1 x 10(6) HUCB-derived MSCs were transplanted through the basilar artery 1 day after ischemic induction using an endovascular interventional approach. In the control group (n = 5), phosphate-buffered saline (PBS) was injected in the same manner in as the HUCBC group. Upon neurobehavioral examination, earlier recovery was observed in the HUCBC group. The HUCBC group showed a decrease in the infarction volume at 1 week after cerebral ischemic induction, whereas the control group showed an increase in the infarction volume at 1 week, by magnetic resonance image analysis. Transplanted cells had differentiated into neurons and astrocytes and were observed in and around endothelial cells that were positive for von Willebrand factor (vWF). HUCB-derived MSCs expressed neuroprotective factors, such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), at 4 weeks after the transplantation. The transplanted cells demonstrated their efficacy by reducing the infarction lesion volume and through earlier recovery from the neurological deficit. These results suggest that intraarterial transplantation of HUCB-derived MSCs could be useful in clinical treatment of cerebral ischemia.

Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model.

Mesenchymal stem cells (MSCs) secrete bioactive factors that exert diverse responses in vivo. In the present study, we explored mechanism how MSCs may lead to higher functional recovery in the animal stroke model. Bone marrow-derived MSCs were transplanted into the brain parenchyma 3 days after induction of stroke by occluding middle cerebral artery for 2 h. Stoke induced proliferation of resident neural stem cells in subventricular zone. However, most of new born cells underwent cell death and had a limited impact on functional recovery after stroke. Transplantation of MSCs enhanced proliferation of endogenous neural stem cells while suppressing the cell death of newly generated cells. Thereby, newborn cells migrated toward ischemic territory and differentiated in ischemic boundaries into doublecortin+ neuroblasts at higher rates in animals with MSCs compared to control group. The present study indicates that therapeutic effects of MSCs are at least partly ascribed to dual functions of MSCs by enhancing endogenous neurogenesis and protecting newborn cells from deleterious environment. The results reinforce the prospects of clinical application using MSCs in the treatment of neurological disorders.

Neural induction with neurogenin1 increases the therapeutic effects of mesenchymal stem cells in the ischemic brain.

Mesenchymal stem cells (MSCs) have been shown to ameliorate a variety of neurological dysfunctions. This effect is believed to be mediated by their paracrine functions, since these cells rarely differentiate into neuronal cells. It is of clinical interest whether neural induction of MSCs is beneficial for the replacement therapy of neurological diseases. Here we report that expression of Neurogenin1 (Ngn1), a proneural gene that directs neuronal differentiation of progenitor cells during development, is sufficient to convert the mesodermal cell fate of MSCs into a neuronal one. Ngn1-expressing MSCs expressed neuron-specific proteins, including NeuroD and voltage-gated Ca2+ and Na+ channels that were absent in parental MSCs. Most importantly, transplantation of Ngn1-expressing MSCs in the animal stroke model dramatically improved motor functions compared with the parental MSCs. MSCs with Ngn1 populated the ischemic brain, where they expressed mature neuronal markers, including microtubule associated protein 2, neurofilament 200, and vesicular glutamate transporter 2, and functionally connected to host neurons. MSCs with and without Ngn1 were indistinguishable in reducing the numbers of Iba1+, ED1+ inflammatory cells, and terminal deoxynucleotidyl transferase dUTP nick-end labeling(+) apoptotic cells and in increasing the numbers of proliferating Ki67+ cells. The data indicate that in addition to the intrinsic paracrine functions of MSCs, motor dysfunctions were remarkably improved by MSCs able to transdifferentiate into neuronal cells. Thus, neural induction of MSCs is advantageous for the treatment of neurological dysfunctions.