Pallav Kolli, Fabio Settecase, Matthew Amans, and Robert Taylor from UCSF, Tim Roberts from University of Pennsylvania
Funding Sources
NIH National Heart Lung Blood Institute (NHLBI) Award (M. Wilson): 1R01HL076486 American Society of Neuroradiology Research and Education Foundation Scholar Award (S. Hetts)
NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) Award (S. Hetts): 1R01EB012031

1. Microcoil Fabrication
<ol>
 <li>Obtain a commercially available microcatheter (e.g. 2.3F Rapid Transit Cordis Neurovascular Catheter, Raynham, MA) for a substrate.</li>
 <li>Ensure catheters have no ferrous components, are considered MR-safe, and range in size 2.3-3.0 F.</li>
 <li>Sputter a titanium adhesion layer followed by a copper seed layer unto a 1 to 2 mm OD insulating tube. Possible materials include polyimide or alumina (Ortech Advanced Ceramics, Sacramento, CA).</li>
 <li>Electrodeposit a positive photoresist layer using Shipley's PEPR-2400 (currently being sold by DOW Chemical under the name Intervia 3D-P). Electrodeposition results in a uniform coating on the non-planar cylindrical surface.</li>
 <li>Photoresist is exposed by a unique laser direct-write system (laser lathe, a non-commercial system developed at Lawrence Livermore National Laboratory) in the pattern of the desired coil form (Figure 2A). This is a modification of the technique originally described in Malba et al.14</li>
 <li>Develop the exposed photoresist in a 1% solution of potassium carbonate at 35 &deg;C.</li>
 <li>Copper is electroplated through the remaining resist mask to form the desired coil. The system can fabricate both solenoid and Helmholtz (racetrack) copper patterns (Figures 2C and 2D).</li>
 <li>After copper electrodeposition, remove the resist with hot developer. Remove the copper seed layer, followed by the titanium adhesion layer.</li>
 <li>Attach the insulating tube to the catheter tip using shrink wrap to complete the assembly. Ensure that the shrink wrap covers the entire coiled tip. To assemble multi-axis catheters place insulating tube structures inside each other as shown in Figure 2E.</li>
 <li>Thread copper wires through the lumen of the microcatheter and solder to the coils at the tip.</li>
 <li>Modify and shorten a 6 ft RJ11 phone cable to 3 ft in length.</li>
 <li>Connect the copper wires emanating from the back end hub of the microcatheter to the modified 3 ft phone jack transmission line.</li>
</ol>
2. Waterbath Setup
<ol>
 <li>Make a small hole in the center of the side of a plastic basin about 5 cm from the bottom.</li>
 <li>Insert a 9F Avanti Cordis vascular sheath (Cordis Endovascular, Miami Lakes, FL) through the hole.</li>
 <li>Cut the distal tip of the vascular sheath leaving a 4 cm-long piece extending in to the basin.</li>
 <li>At the end of the sheath, attach a rotating hemostatic or Thuoy-Borst valve to stabilize the location of the microcatheter.</li>
 <li>Fill the basin with distilled water ensuring complete submersion of the apparatus.</li>
 <li>Insert the catheter with coiled tip through the vascular sheath and valve.</li>
 <li>Measure and record the unrestrained length of the microcatheter extending from the valve in to the waterbath.</li>
 <li>Place the waterbath with microcatheter system within the magnet of the MR scanner and orient with respect to the bore of the magnet.</li>
 <li>Connect the modified 3 ft phone cable attached to the catheter to a 25 ft RJ11 phone cable transmission line using a 2-way phone jack.</li>
 <li>Connect the other end of the 25 ft phone cable to a Lambda LPD-422A-FM dual regulated power supply to deliver up to 1 A of current to the device.</li>
 <li>Place the transmission lines through a waveguide and the power source outside of the MR scanner room outside of the 5 Gauss line.</li>
</ol>
3. Vessel Phantom Setup
<ol>
 <li>Construct a hollow vessel phantom with a Y-shaped intersection from rubber tubing prior to experimentation.</li>
 <li>Fill the vessel phantom with a 0.0102 M solution of gadopentetate dimeglumine (GdDTPA) (Magnevist, Bayer Healthcare Pharmaceuticals, Montville, New Jersey) in distilled water to create contrast between the phantom vessels and background.</li>
 <li>Assemble the microcatheter system as outlined in steps 1.1 through 1.9. Connect the catheter to the power supply and position as described in steps 2.9 to 2.11.</li>
 <li>Position the tip of the microcatheter at the base of the vessel opening.</li>
 <li>Place the phantom within the magnet of the MR scanner and orient with respect to the bore of the magnet.</li>
</ol>
4. Magnetic Resonance Imaging
<ol>
 <li>Perform imaging with a 1.5T clinical MR system (Siemens Avanto, SW: Syngo B13, Erlangen, Germany; Philips Achieva, SW release 2.1, Cleveland, OH).</li>
 <li>Apply &lt;50 mA of current to visualize the catheter tip position. Under MRI, a small magnetic moment will be produced at the catheter tip to visualize a distinct artifact of varying shape depending on which coils are energized.</li>
 <li>Apply variable amounts of current in the range of &plusmn;100 mA from the Lambda dual power source to the coils and observe tip deflection (Figures 3A-3C) in the water bath setup. Because tip deflection is almost instantaneous, current need only be applied for ~1-2 sec to visualize maximum deflection.</li>
 <li>Repeat and record consecutive applications of set amounts of current.</li>
 <li>Repeat step 4.2 while simultaneously pushing the catheter by hand allowing mechanical advancement through the vessel phantom (Figures 4A and 4B). Apply current at the branch point to deflect the catheter tip into the desired vessel. Advance the catheter into the branch vessel by manually pushing the catheter end (Figure 4C). Retract the catheter to the vessel bifurcation and repeat in the opposite branch (Figure 4D).</li>
 <li>Acquire MR images using a 2D snapshot-FLASH sequence (TR=30 msec, TE=1.4 msec, a matrix of 256 x128 and flip angle ~30 &deg;).</li>
</ol>
5. Deflection Measurements
Analyze and measure angle deflections of images captured during water bath experiments with various computer applications (any Digital Imaging and Communications in Medicine (DICOM) Viewer).

<ol>
	<li>Molyneux, A. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=International+subarachnoid+aneurysm+trial+(ISAT)+of+neurosurgical+clipping+versus+endovascular+coiling+in+2143+patients+with+ruptured+intracranial+aneurysms:+a+randomised+comparison+of+effects+on+survival,+dependency,+seizures,+rebleeding,+subgroups,+and+aneurysm+occlusion.">International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion.</a> Lancet. 366, 809-817 (2005).</li><li>Razavi, M. 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L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endovascular+technology+and+its+impact+on+the+relationships+among+vascular+surgeons,+interventional+radiologists,+and+other+specialists.">Endovascular technology and its impact on the relationships among vascular surgeons, interventional radiologists, and other specialists.</a> World J. Surg. 20, 687-691 (1996).</li><li>Miller, D. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+radiation+management+for+fluoroscopically+guided+interventional+procedures.">Clinical radiation management for fluoroscopically guided interventional procedures.</a> Radiology. 257, 321-332 .</li><li>Balter, S., Hopewell, J. W., Miller, D. L., Wagner, L. K., Zelefsky, M. 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K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Skin+injuries+from+fluoroscopically+guided+procedures:+part+1,+characteristics+of+radiation+injury.">Skin injuries from fluoroscopically guided procedures: part 1, characteristics of radiation injury.</a> AJR Am. J. Roentgenol. 177, 3-11 (2001).</li><li>Koenig, T. R., Mettler, F. A., Wagner, L. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Skin+injuries+from+fluoroscopically+guided+procedures:+part+2,+review+of+73+cases+and+recommendations+for+minimizing+dose+delivered+to+patient.">Skin injuries from fluoroscopically guided procedures: part 2, review of 73 cases and recommendations for minimizing dose delivered to patient.</a> AJR Am. J. Roentgenol. 177, 13-20 (2001).</li><li>Arenson, R. L. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetically+directable+remote+guidance+systems,+and+methods+and+use+thereof.">Magnetically directable remote guidance systems, and methods and use thereof.</a> United States Patent. , (2001).</li><li>Roberts, T. P., Hassenzahl, W. V., Hetts, S. W., Arenson, R. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Remote+control+of+catheter+tip+deflection:+an+opportunity+for+interventional+MRI.">Remote control of catheter tip deflection: an opportunity for interventional MRI.</a> Magn. Reson. Med. 48, 1091-1095 (2002).</li><li>Malba, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Laser-lathe+lithography+-+a+novel+method+for+manufacturing+nuclear+magnetic+resonance+microcoils.">Laser-lathe lithography - a novel method for manufacturing nuclear magnetic resonance microcoils.</a> Biomed. Microdevices. 5, 21-27 (2003).</li><li>Bernhardt, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Steerable+catheter+microcoils+for+interventional+MRI+reducing+resistive+heating.">Steerable catheter microcoils for interventional MRI reducing resistive heating.</a> Academic radiology. 18, 270-276 (2011).</li><li>Muller, L., Saeed, M., Wilson, M. W., Hetts, S. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Remote+control+catheter+navigation:+options+for+guidance+under+MRI.">Remote control catheter navigation: options for guidance under MRI.</a> Journal of Cardiovascular Magnetic Resonance : Official Journal of the Society for Cardiovascular Magnetic Resonance. 14, 33 (2012).</li><li>Wilson, M. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+catheter+manipulation+in+the+interventional+MRI+environment.">Magnetic catheter manipulation in the interventional MRI environment.</a> J. Vasc. Interv. Radiol. , (2013).</li></ol>

Dr. Hetts has received grant support from Stryker Corporation and is a paid consultant for Silk Road Medical, Inc.

Here we describe the protocol for deflection of a microcatheter in a MR scanner. The key parameters for success are accurate application of current and measurement of deflection angle. Inaccurate measurement of deflection angle is the most probable error encountered in this protocol. The angles captured in MR images during the waterbath experiment may differ from actual values due to slight differences in the orientation by which the medium is positioned with respect to the bore of the magnet. To address this issue in th...

Endovascular procedures performed in interventional medicine use x-ray guidance as a tool for catheter navigation through vasculature to treat several major illnesses, such as brain aneurysm, ischemic stroke, solid tumors, atherosclerosis and cardiac arrhythmias targeting over one million patients per year worldwide1-5. With the use of contrast media, navigation through vasculature is achieved through manual rotation of the catheter and mechanical advancement by the interventionist's hand6. However, navigation through small tortuous blood vessels around many vascular bends becomes increasingly difficult, elongating the time before reaching the target site. This poses a problem for time-sensitive procedures such as the removal of a clot in an occluded blood vessel. Additionally, prolonged procedures increase the radiation dose and create the potential for adverse events7-11. However, endovascular procedures performed under magnetic resonance imaging may provide a solution.
 The strong homogenous magnetic field of an MRI scanner can be exploited for catheter tip navigation by remote control12,13. Current applied to a microcoil located at a catheter tip induces a small magnetic moment, which experiences a torque as it aligns with the bore of the MRI scanner13 (Figure 1). If electric current is activated in an individual coil, the catheter tip can be deflected in one plane by remote control. If three coils at a catheter tip are energized, catheter tip deflection can be achieved in three-dimension. Thus, magnetically facilitated steering of a catheter has the potential to increase the speed and efficacy of vascular navigation in endovascular procedures, which could reduce procedure times and improve patient outcomes. In this study, we examined if current applied to a microcoil-tipped endovascular catheter can produce reliable and controlled deflections under MR-guidance as preliminary testing of catheter navigation studies.

<table border="1">
<tbody>
 <tr>
 <td>Name of Reagent/Material</td>
 <td>Company</td>
 <td>Catalog Number</td>
 <td>Comments</td>
 </tr>
 <tr>
 <td>GdDTPA Contrast Media (Magnevist)</td>
 <td>Bayer HealthCare Pharmaceuticals Inc. </td>
 <td>1240340</td>
 <td>McKesson Material Number</td>
 </tr>
 <tr>
 <td>Positive Photoresist</td>
 <td>Shipley</td>
 <td>N/A</td>
 <td>PEPR-2400, Replacement: Dow Chemicals Intervia 3D-P </td>
 </tr>
 <tr>
 <td>Copper Sulfate</td>
 <td>ScienceLab</td>
 <td>SLC3778</td>
 <td>Crystal form</td>
 </tr>
 <tr>
 <td>Sulfuric Acid</td>
 <td>ScienceLab</td>
 <td>SLS1573</td>
 <td>50% w/w solution</td>
 </tr>
 <tr>
 <td>Parrafin Wax</td>
 <td>Carolina</td>
 <td>879190</td>
 <td></td>
 </tr>
 <tr>
 <td>Potassium Carbonate </td>
 <td>Acros Organics</td>
 <td>424081000</td>
 <td></td>
 </tr>
</tbody>
 </table>

magnetically-assisted remote controlled microcatheter tip deflection under magnetic resonance imaging

X-ray fluoroscopy-guided endovascular procedures have several significant limitations, including difficult catheter navigation and use of ionizing radiation, which can potentially be overcome using a magnetically steerable catheter under MR guidance.
	The main goal of this work is to develop a microcatheter whose tip can be remotely controlled using the magnetic field of the MR scanner. This protocol aims to describe the procedures for applying current to the microcoil-tipped microcatheter to produce consistent and controllable deflections.
	A microcoil was fabricated using laser lathe lithography onto a polyimide-tipped endovascular catheter. In vitro testing was performed in a waterbath and vessel phantom under the guidance of a 1.5-T MR system using steady-state free precession (SSFP) sequencing. Various amounts of current were applied to the coils of the microcatheter to produce measureable tip deflections and navigate in vascular phantoms.
	The development of this device provides a platform for future testing and opportunity to revolutionize the endovascular interventional MRI environment.

From the protocol described above, an angle of deflection between 0 and 90 degrees should be observed from application of 50-300 mA of current delivered simultaneously to both coils of a combined solenoid and Helmholtz coil microcatheter system (Figure 2E). An increase in applied current should result in an increase in microcatheter deflection angle, while a reversal in current polarity should result in deflection in the exact opposite direction as observed with positive current (Figures 5A-5C</s...

Watch this Scientific Journal Video about Magnetically-Assisted Remote Controlled Microcatheter Tip Deflection under Magnetic Resonance Imaging at JoVE.com

Magnetically-Assisted Remote Controlled Microcatheter Tip Deflection under Magnetic Resonance Imaging

Current applied to an endovascular microcatheter with microcoil tip made by laser lathe lithography can achieve controllable deflections under magnetic resonance (MR) guidance, which may improve speed and efficacy of navigation of vasculature during various endovascular procedures.

X-ray fluoroscopy-guided  endovascular procedures have several significant limitations, including  difficult catheter navigation and use of ionizing ...

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12.3K Views.  University of California, San Francisco. Ток, приложенный к эндоваскулярной микрокатетер с microcoil наконечник сделан по лазерной литографии токарный станок может достичь управляемой прогибов под магнитного резонанса (МР) руководство, которое может улучшить скорость и эффективность навигации сосуди?...

Video: Magnetically-Assisted Remote Controlled Microcatheter Tip Deflection under Magnetic Resonance Imaging

Magnetic Resonance Elastography Methodology for the Evaluation of Tissue Engineered Construct Growth

Traditional mechanical testing often results in the destruction of the sample, and in the case of long term tissue engineered construct studies, the use of destructive assessment is not acceptable. A proposed alternative is the use of an imaging process called magnetic resonance elastography. Elastography is a nondestructive method for determining the engineered outcome by measuring local mechanical property values (i.e., complex shear modulus), which are essential markers for identifying the structure and functionality of a tissue. As a noninvasive means for evaluation, the monitoring of engineered constructs with imaging modalities such as magnetic resonance imaging (MRI) has seen increasing interest in the past decade1. For example, the magnetic resonance (MR) techniques of diffusion and relaxometry have been able to characterize the changes in chemical and physical properties during engineered tissue development2. The method proposed in the following protocol uses microscopic magnetic resonance elastography (&mu;MRE) as a noninvasive MR based technique for measuring the mechanical properties of small soft tissues3. MRE is achieved by coupling a sonic mechanical actuator with the tissue of interest and recording the shear wave propagation with an MR scanner4. Recently, &mu;MRE has been applied in tissue engineering to acquire essential growth information that is traditionally measured using destructive mechanical macroscopic techniques5. In the following procedure, elastography is achieved through the imaging of engineered constructs with a modified Hahn spin-echo sequence coupled with a mechanical actuator. As shown in Figure 1, the modified sequence synchronizes image acquisition with the transmission of external shear waves; subsequently, the motion is sensitized through the use of oscillating bipolar pairs. Following collection of images with positive and negative motion sensitization, complex division of the data produce a shear wave image. Then, the image is assessed using an inversion algorithm to generate a shear stiffness map6. The resulting measurements at each voxel have been shown to strongly correlate (R2&gt;0.9914) with data collected using dynamic mechanical analysis7. In this study, elastography is integrated into the tissue development process for monitoring human mesenchymal stem cell (hMSC) differentiation into adipogenic and osteogenic constructs as shown in Figure 2.

The procedure demonstrates the methodology of magnetic resonance elastography for monitoring the engineered outcome of adipose and osteogenic tissue engineered constructs through noninvasive local assessment of the mechanical properties using microscopic magnetic resonance elastography (&mu;MRE).

Traditional mechanical testing often results in the destruction of the sample, and in the case of long term tissue engineered construct studies, the use ...

Remote Magnetic Actuation of Micrometric Probes for in situ 3D Mapping of Bacterial Biofilm Physical Properties

Bacterial adhesion and growth on interfaces lead to the formation of three-dimensional heterogeneous structures so-called biofilms. The cells dwelling in these structures are held together by physical interactions mediated by a network of extracellular polymeric substances. Bacterial biofilms impact many human activities and the understanding of their properties is crucial for a better control of their development &#8212; maintenance or eradication &#8212; depending on their adverse or beneficial outcome. This paper describes a novel methodology aiming to measure in situ the local physical properties of the biofilm that had been, until now, examined only from a macroscopic and homogeneous material perspective. The experiment described here&#160;involves introducing magnetic particles into a growing biofilm to seed local probes that can be remotely actuated without disturbing the structural properties of the biofilm. Dedicated magnetic tweezers were developed to exert a defined force on each particle embedded in the biofilm. The setup is mounted on the stage of a microscope to enable the&#160;recording of time-lapse images of the particle-pulling period. The particle trajectories are then extracted from the pulling sequence and the local viscoelastic parameters are derived from each particle displacement curve, thereby providing the 3D-spatial distribution of the parameters. Gaining insights into the biofilm mechanical profile is essential from an engineer&#39;s point of view for biofilm control purposes but also from a fundamental perspective to clarify the relationship between the architectural properties and the specific biology of these structures.

Remote Magnetic Actuation of Micrometric Probes for in situ 3D Mapping of Bacterial Biofilm Physical Properties

This paper shows an original methodology based on the remote actuation of magnetic particles seeded in a bacterial biofilm and the development of dedicated magnetic tweezers to measure in situ the local mechanical properties of the complex living material built by micro-organisms at interfaces.

Bacterial adhesion and growth on interfaces lead to the formation of three-dimensional heterogeneous structures so-called biofilms. The cells dwelling in ...

Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e.,&#160;gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.

AN MRI-compatible&#160;custom-designed laser-based heating apparatus has been developed to provide local heating of subcutaneous tumors in order to activate release of agents from thermosensitive liposomes specifically at the tumor region.

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect ...

Alternating Magnetic Field-Responsive Hybrid Gelatin Microgels for Controlled Drug Release

Magnetically-responsive nano/micro-engineered biomaterials that enable a tightly controlled, on-demand drug delivery have been developed as new types of smart soft devices for biomedical applications. Although a number of magnetically-responsive drug delivery systems have demonstrated efficacies through either in vitro proof of concept studies or in vivo preclinical applications, their use in clinical settings is still limited by their insufficient biocompatibility or biodegradability. Additionally, many of the existing platforms rely on sophisticated techniques for their fabrications. We recently demonstrated the fabrication of biodegradable, gelatin-based thermo-responsive microgel by physically entrapping poly(N-isopropylacrylamide-co-acrylamide) chains as a minor component within a three-dimensional gelatin network. In this study, we present a facile method to fabricate a biodegradable drug release platform that enables a magneto-thermally triggered drug release. This was achieved by incorporating superparamagnetic iron oxide nanoparticles and thermo-responsive polymers within gelatin-based colloidal microgels, in conjunction with an alternating magnetic field application system.

We present a facile method to fabricate a biodegradable gelatin-based drug release platform that is magneto-thermally responsive. This was achieved by incorporating superparamagnetic iron oxide nanoparticles and poly(N-isopropylacrylamide-co-acrylamide) within a spherical gelatin micro-network crosslinked by genipin, in conjunction with an alternating magnetic field application system.

Magnetically-responsive nano/micro-engineered biomaterials that enable a tightly controlled, on-demand drug delivery have been developed as new types of ...

Rapid Scan Electron Paramagnetic Resonance Opens New Avenues for Imaging Physiologically Important Parameters In Vivo

We demonstrate a superior method of 2D spectral-spatial imaging of stable radical reporter molecules at 250 MHz using rapid-scan electron-paramagnetic-resonance (RS-EPR), which can provide quantitative information under in vivo conditions on oxygen concentration, pH, redox status and concentration of signaling molecules (i.e., OH&#8226;, NO&#8226;). The RS-EPR technique has a higher sensitivity, improved spatial resolution (1 mm), and shorter acquisition time in comparison to the standard continuous wave (CW) technique. A variety of phantom configurations have been tested, with spatial resolution varying from 1 to 6 mm, and spectral width of the reporter molecules ranging from 16 &#181;T (160 mG) to 5 mT (50 G). A cross-loop bimodal resonator decouples excitation and detection, reducing the noise, while the rapid scan effect allows more power to be input to the spin system before saturation, increasing the EPR signal. This leads to a substantially higher signal-to-noise ratio than in conventional CW EPR experiments.

Rapid Scan Electron Paramagnetic Resonance Opens New Avenues for Imaging Physiologically Important Parameters In Vivo

A new electron paramagnetic resonance (EPR) method, rapid scan EPR (RS-EPR), is demonstrated for 2D spectral spatial imaging which is superior to the traditional continuous wave (CW) technique and opens new venues for in vivo imaging. Results are demonstrated at 250 MHz, but the technique is applicable at any frequency.

We demonstrate a superior method of 2D spectral-spatial imaging of stable radical reporter molecules at 250 MHz using rapid-scan ...

Magnetic Levitation Coupled with Portable Imaging and Analysis for Disease Diagnostics

Currently, many clinical diagnostic procedures are complex, costly, inefficient, and inaccessible to a large population in the world. The requirements for specialized equipment and trained personnel require that many diagnostic tests be performed at remote, centralized clinical laboratories. Magnetic levitation is a simple yet powerful technique and can be applied to levitate cells, which are suspended in a paramagnetic solution and placed in a magnetic field, at a position determined by equilibrium between a magnetic force and a buoyancy force. Here, we present a versatile platform technology designed for point-of-care diagnostics which uses magnetic levitation coupled to microscopic imaging and automated analysis to determine the density distribution of a patient's cells as a useful diagnostic indicator. We present two platforms operating on this principle: (i) a smartphone-compatible version of the technology, where the built-in smartphone camera is used to image cells in the magnetic field and a smartphone application processes the images and to measures the density distribution of the cells and (ii) a self-contained version where a camera board is used to capture images and an embedded processing unit with attached thin-film-transistor (TFT) screen measures and displays the results. Demonstrated applications include: (i) measuring the altered distribution of a cell population with a disease phenotype compared to a healthy phenotype, which is applied to sickle cell disease diagnosis, and (ii) separation of different cell types based on their characteristic densities, which is applied to separate white blood cells from red blood cells for white blood cell cytometry. These applications, as well as future extensions of the essential density-based measurements enabled by this portable, user-friendly platform technology, will significantly enhance disease diagnostic capabilities at the point of care.

We present a magnetic levitation technique coupled with automated imaging and analysis in both a smartphone-compatible device and a device with embedded imaging and processing. This is applied to measure the density distribution of cells with two demonstrated biomedical applications: sickle cell disease diagnosis and separating white and red blood cells.

Currently, many clinical diagnostic procedures are complex, costly, inefficient, and inaccessible to a large population in the world. The requirements for ...

Magnetic and Thermal-sensitive Poly(N-isopropylacrylamide)-based Microgels for Magnetically Triggered Controlled Release

Magnetically and thermally sensitive poly(N-isopropylacrylamide) (PNIPAAm)/Fe3O4-NH2 microgels with the encapsulated anti-cancer drug curcumin (Cur) were designed and fabricated for magnetically triggered release. PNIPAAm-based magnetic microgels with a spherical structure were produced via a temperature-induced emulsion followed with physical-crosslinking by mixing PNIPAAm, polyethylenimine (PEI), and Fe3O4-NH2 magnetic nanoparticles. Because of their dispersity, the Fe3O4-NH2 nanoparticles were embedded inside the polymer matrix. The amine groups exposed on the Fe3O4-NH2 and PEI surface supported the spherical structure by physically crosslinking with the amide groups of the PNIPAAm. The hydrophobic anti-cancer drug curcumin can be dispersed in water after encapsulation into the microgels. The microgels were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and UV-Vis spectral analysis. Furthermore, magnetically triggered release was studied under an external high frequency magnetic field (HFMF). A significant &#34;burst release&#34; of curcumin was observed after applying the HFMF to the microgels due to the magnetic inductive heating (hyperthermia) effect. This manuscript describes the magnetically triggered controlled release of Cur-PNIPAAm/Fe3O4-NH2 encapsulated curcumin, which can be potentially applied for tumor therapy.

Magnetic and Thermal-sensitive PolyN-isopropylacrylamide-based Microgels for Magnetically Triggered Controlled Release

This manuscript describes the preparation of magnetic and thermal-sensitive microgels via a temperature-induced emulsion without chemical reaction. These sensitive microgels were synthesized by mixing poly(N-isopropylacrylamide) (PNIPAAm), polyethylenimine (PEI) and Fe3O4-NH2 nanoparticles for the potential use in magnetically and thermally triggered drug-release.

Magnetically and thermally sensitive poly(N-isopropylacrylamide) (PNIPAAm)/Fe3O4-NH2 microgels with the encapsulated anti-cancer drug curcumin (Cur) were ...

Metabolic Support of Excised, Living Brain Tissues During Magnetic Resonance Microscopy Acquisition

This protocol describes the procedures necessary to support normal metabolic functions of acute brain slice preparations during the collection of magnetic resonance (MR) microscopy data. While it is possible to perform MR collections on living, excised mammalian tissue, such experiments have traditionally been constrained by resolution limits and are thus incapable of visualizing tissue microstructure. Conversely, MR protocols that did achieve microscopic image resolution required the use of fixed samples to accommodate the need for static, unchanging conditions over lengthy scan times. The current protocol describes the first available MR technique that enables imaging of living, mammalian tissue samples at microscopic resolutions. Such data is of great importance to the understanding of how pathology-based contrast changes occurring at the microscopic level influence the content of macroscopic MR scans such as those used in the clinic. Once such an understanding is realized, diagnostic methods with greater sensitivity and accuracy can be developed, which will translate directly to earlier disease treatment, more accurate therapy monitoring and improved patient outcomes.
While the described methodology focuses on brain slice preparations, the protocol is adaptable to any excised tissue slice given that changes are made to the gas and perfusate preparations to accommodate the tissue&#39;s specific metabolic needs. Successful execution of the protocol should result in living, acute slice preparations that exhibit MR diffusion signal stability for periods up to 15.5 h. The primary advantages of the current system over other MR compatible perfusion apparatuses are its compatibility with the MR microscopy hardware required to attain higher resolution images and ability to provide constant, uninterrupted flow with carefully regulated perfusate conditions. Reduced sample throughput is a consideration with this design as only one tissue slice may be imaged at a time.

The current protocol describes a method by which users can maintain viability of acute hippocampal and cortical slice preparations during the collection of magnetic resonance microscopy data.

This protocol describes the procedures necessary to support normal metabolic functions of acute brain slice preparations during the collection of magnetic ...

Measuring the Spin-Lattice Relaxation Magnetic Field Dependence of Hyperpolarized [1-13C]pyruvate

The fundamental limit to in vivo imaging applications of hyperpolarized 13C-enriched compounds is their finite spin-lattice relaxation times. Various factors affect the relaxation rates, such as buffer composition, solution pH, temperature, and magnetic field. In this last regard, the spin-lattice relaxation time can be measured at clinical field strengths, but at lower fields, where these compounds are dispensed from the polarizer and transported to the MRI, the relaxation is even faster and difficult to measure. To have a better understanding of the amount of magnetization lost during transport, we used fast field-cycling relaxometry, with magnetic resonance detection of 13C nuclei at ~0.75 T, to measure the nuclear magnetic resonance dispersion of the spin-lattice relaxation time of hyperpolarized [1-13C]pyruvate. Dissolution dynamic nuclear polarization was used to produce hyperpolarized samples of pyruvate at a concentration of 80 mmol/L and physiological pH (~7.8). These solutions were rapidly transferred to a fast field-cycling relaxometer so that relaxation of the sample magnetization could be measured as a function of time using a calibrated small flip angle (3&#176;-5&#176;). To map the T1 dispersion of the C-1 of pyruvate, we recorded data for different relaxation fields ranging between 0.237 mT and 0.705 T. With this information, we determined an empirical equation to estimate the spin-lattice relaxation of the hyperpolarized substrate within the mentioned range of magnetic fields. These results can be used to predict the amount of magnetization lost during transport and to improve experimental designs to minimize signal loss.

Measuring the Spin-Lattice Relaxation Magnetic Field Dependence of Hyperpolarized [1-13C]pyruvate

We present a protocol to measure the magnetic field dependence of the spin-lattice relaxation time of 13C-enriched compounds, hyperpolarized by means of dynamic nuclear polarization, using fast field-cycled relaxometry. Specifically, we have demonstrated this with [1-13C]pyruvate, but the protocol could be extended to other hyperpolarized substrates.

The fundamental limit to in vivo imaging applications of hyperpolarized 13C-enriched compounds is their finite spin-lattice relaxation times. Various ...

High-resolution Imaging of Nuclear Dynamics in Live Cells under Uniaxial Tensile Strain

Extracellular mechanical strain is known to elicit cell phenotypic responses and has physiological relevance in several tissue systems. To capture the effect of applied extracellular tensile strain on cell populations in vitro via biochemical assays, a device has previously been designed which can be fabricated simply and is small enough to fit inside tissue culture incubators, as well as on top of microscope stages. However, the previous design of the polydimethylsiloxane substratum did not allow high-resolution subcellular imaging via oil-immersion objectives. This work describes a redesigned geometry of the polydimethylsiloxane substratum and a customized imaging setup that together can facilitate high-resolution subcellular imaging of live cells while under applied strain. This substratum can be used with the same, earlier designed device and, hence, has the same advantages as listed above, in addition to allowing high-resolution optical imaging. The design of the polydimethylsiloxane substratum can be improved by incorporating a grid which will facilitate tracking the same cell before and after the application of strain. Representative results demonstrate high-resolution time-lapse imaging of fluorescently labeled nuclei within strained cells captured using the method described here. These nuclear dynamics data give insights into the mechanism by which applied tensile strain promotes differentiation of oligodendrocyte progenitor cells.&#160;

Using a previously designed device to apply mechanical strain to adherent cells, this paper describes a redesigned substratum geometry and a customized apparatus for high-resolution single-cell imaging of strained cells with a 100x oil immersion objective.

Extracellular mechanical strain is known to elicit cell phenotypic responses and has physiological relevance in several tissue systems. To capture the ...