WO2010020938A1

WO2010020938A1 - Ultrasound enhanced stem cell delivery device and method

Info

Publication number: WO2010020938A1
Application number: PCT/IB2009/053625
Authority: WO
Inventors: Christopher Stephen Hall; Chien Ting Chin; Klaus Tiemann; Alexander Ghanem
Original assignee: Rheinische Friedrich Wilhelms Universitaet Bonn; Koninklijke Philips Electronics NV
Current assignee: Rheinische Friedrich Wilhelms Universitaet Bonn; Koninklijke Philips NV
Priority date: 2008-08-18
Filing date: 2009-08-17
Publication date: 2010-02-25
Anticipated expiration: 2011-02-18

Abstract

A method of delivering cell sized objects to a targeted organ or tissue of interest comprises: introducing (64, 70) the cell sized objects into the bloodstream; introducing (50, 70) microbubbles into the bloodstream; and locally agitating (56, 76) the introduced microbubbles, the agitating being substantially localized to the targeted organ or tissue of interest, the local agitating of the introduced microbubbles enhancing transendothelial migration of the cell sized objects into the targeted organ or tissue of interest. An apparatus for performing said method comprises: an intravascular delivery device (20, 22, 24) configured to deliver the cell sized objects and microbubbles into the bloodstream; an ultrasound system (30, 32, 34, 36); and a therapy controller (44) configured to control delivery of the cell-sized objects and the microbubbles into the bloodstream and ultrasonic agitation of the intravascular microbubbles in the targeted organ or tissue of interest.

Description

ULTRASOUND ENHANCED STEM CELL DELIVERY DEVICE AND METHOD

DESCRIPTION

The following relates to the medical arts and related arts. It finds particular application in delivery of stem cells to a targeted organ or tissue, and is described with particular reference thereto. The following is generally applicable to targeted intravascular (i.e., intravenous or intra-arterial) delivery of stem cells, drug delivery microcapsules, micromachines, or other cell-sized objects to a targeted organ or tissue of interest.

Some stem cell therapies entail delivery of undifferentiated or partially differentiated stem cells to an organ or tissue of interest. Once at the organ or tissue of interest, the stem cells multiply by mitosis and differentiate in a manner comporting with the targeted biological environment so as to replace injured or dead cells and rejuvenate or heal the organ or tissue of interest. The stem cells may be derived from various sources, such as adult stem cells, bone marrow stem cells, embryonic or placental stem cells, or so forth.

Achieving effective and efficient targeted delivery of the stem cells to the targeted organ or tissue of interest has heretofore been problematic.

One delivery approach is an intra-organ injection in which a catheter or other interventional instrument is inserted directly into musculature of the targeted organ or into tissue of interest so as to provide direct delivery of the stem cells. This approach is highly invasive, and has exhibited some adverse consistency issues. Another approach for stem cell delivery that has been attempted is intravascular delivery. Here, the stem cells are injected into the blood stream in the hope that some stem cells will collect in the targeted organ or tissue of interest. This approach has the disadvantage of being a poorly targeted delivery system. In many cases a large majority of the stem cells end up being removed by the spleen or other blood filtering organs of the body.

The following provides new and improved apparatuses and methods which overcome the above-referenced problems and others.

In accordance with one disclosed aspect, a method of delivering cell-sized objects to a targeted organ or tissue of interest comprises: introducing the cell sized objects into the bloodstream; introducing microbubbles into the bloodstream; and locally agitating the introduced microbubbles, the agitating being substantially localized to the targeted organ or tissue of interest, the local agitating of the introduced microbubbles enhancing transendothelial migration of the cell sized objects into the targeted organ or tissue of interest.

In accordance with another disclosed aspect, an apparatus for delivering cell sized objects to a targeted organ or tissue of interest comprises: an intravascular delivery device configured to deliver the cell-sized objects and microbubbles into the bloodstream; and an ultrasound system; and a therapy controller configured to control the intravascular delivery system to control delivery of the cell-sized objects and the microbubbles into the bloodstream and to control the ultrasound system to ultrasonically agitate intravascular microbubbles in the targeted organ or tissue of interest so as to enhance transendothelial migration of the cell-sized objects into the targeted organ or tissue of interest.

In accordance with another disclosed aspect, a method of delivering cell sized objects to a targeted organ or tissue of interest comprises: performing a transendothelial migration-enhancing process on vasculature of the targeted organ or tissue of interest; and introducing the cell sized objects into the bloodstream, the cell sized objects preferentially undergoing transendothelial migration out of the vasculature of the targeted organ or tissue of interest due to the transendothelial migration-enhancing process. One advantage resides in a less invasive or non-invasive delivery mechanism for stem cells or other diagnostic or therapeutic agents.

Another advantage resides in improved targeting of intravascular delivery of stem cells or other cell-sized objects to an organ or tissue of interest.

Another advantage resides in providing targeted intravascular delivery of stem cells or other cell-sized objects to substantially any soft organ or tissue of interest.

Still further advantages of the present invention will be appreciated to those of ordinary skill in the art upon reading and understanding the following detailed description.

FIGURE 1 diagrammatically shows a delivery system for intravascular delivery of cell-sized objects to an organ or tissue of interest.

FIGURE 2 diagrammatically shows a stem cell delivery process suitably performed by the system of FIGURE 1. FIGURE 3 diagrammatically shows another stem cell delivery process suitably performed by the system of FIGURE 1.

With reference to FIGURE 1, a system for delivering cell-sized objects to a targeted organ or tissue of interest is described. A subject 10 is disposed on a subject support 12, such as a table, gurney, chair, or so forth. In the illustrated embodiment, the cell-sized objects to be delivered are stem cells; however, more generally other types of cells may be delivered, or other cell-sized objects may be delivered such as drug delivery microcapsules, micromachines, or so forth. The system provides for intravascular delivery of a stem cells serum 14 containing stem cells or other cell-sized objects for delivery to the organ or tissue of interest.

The intravascular delivery system also delivers microbubbles that are locally agitated in the vasculature of the targeted organ or tissue of interest in order to enhance transendothelial migration of the stem cells or other cell-sized objects into the targeted organ or tissue of interest. In the illustrated embodiment, the microbubbles are in the form of an ultrasonic contrast agent with microbubbles 16, and the microbubbles are agitated in the vasculature by applied ultrasonic energy. In some embodiments, the commercial ultrasonic contrast agent SonoVue™ (available from Bracco Inc., Milano, Italy) is employed. More generally, substantially any kind of gas-filled, lipid-coated microbubbles or other stabilized microbubbles can be used. The use of the illustrated ultrasonic contrast agent with microbubbles 16 advantageously allows the microbubble distribution in the bloodstream to be monitored by ultrasonic imaging. In some embodiments the introduced microbubbles have sizes between about one-half micron and about twenty microns.

In the illustrated embodiment, the intravascular delivery system includes an intravascular delivery controller 20 configured to start and stop delivery of the stem cells serum 14 and of the contrast agent with microbubbles 16 responsive to suitable control signals. In some embodiments, a common intravascular delivery pathway such as a single intravascular tube 22, delivers both the stem cells serum 14 and the contrast agent with microbubbles 16. In this approach, the intravascular delivery controller 20 includes suitable fluid switching valves to introduce a selected one, or both, of the fluids 14, 16 into the intravascular tube 22 for entry into the subject 10. Alternatively, separate intravascular pathways, such as two intravascular tubes 22, 24, can be provided to enable separate delivery of the two fluids 14, 16. Further, although in the illustrated embodiment the ultrasound contrast agent including extant microbubbles 16 is introduced into the bloodstream, in other approaches a the microbubbles may be intravascularly introduced by introducing a gaseous precursor into the bloodstream, which is then converted in the bloodstream into microbubbles by application of ultrasonic energy.

The stem cell delivery techniques disclosed herein make use of the ultrasound-mediated microbubble effect (UME). This technique involves an intravascular injection or infusion of gas-filled lipid-coated microbubbles and localized or focused application of ultrasonic energy to induce oscillation, disruption, or both oscillation and disruption, of microbubbles in a localized vicinity. The mechanical movement of microbubbles under ultrasonic agitation induces cellular response on adjacent endothelium through shear forces and direct deformation. UME is also believed to cause inflammatory action. The UME produces small holes or perturbations in capillaries that may remain for several hours or longer before healing. Thus, after application of ultrasonic energy small transient pores are induced in the capillaries. UME has been used to deliver molecular- sized agents, e.g., genetic material, into targeted tissue. See, e.g. Bekeredjian et al, "Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart", Circulation vol. 108, pp. 1022-26 (2003). UME has also been used in conjunction with intravascular delivery of bone-marrow mononuclear cells or endothelial progenitor cells to promote neocapillary formation in ischemic skeletal muscle tissue and in myocardial tissue. Imada et al., "Targeted Delivery of Bone Marrow Mononuclear Cells by Ultrasound Destruction of Microbubbles Induces Both Angiogenesis and Arteriogenesis Response", Arterioscler. Thromb. Vase. Biol. vol. 25, pp. 2128-34 (2005); Zen et al., Myocardium-targeted delivery of endothelial progenitor cells by ultrasound-mediated microbubble destruction improves cardiac function via angiogenic response", J. MoI. Cell. Cardiol, vol. 40, pp. 799-809 (2006). These applications are directed to neocapillary formation.

The technique of UME is extended as disclosed herein to promote transendothelial migration of cell-sized objects such as stem cells from the bloodstream into an organ or tissue of interest. In the case of molecular- sized agents such as genetic material, transendothelial migration is believed to be enhanced by the weakening or breakdown of cellular membranes induced by UME. While this mechanism may be active in transendothelial migration of stem cells, the inventors have also observed a substantial increase in pro-inflammatory cytokine levels due to UME. The cytokine levels peaked around 15 minutes after the UME. In view of this, it is believed that inflammatory action, possibly coupled with stress-induced biochemical attraction of stem cells to the area stressed by the UME, are also candidate mechisms for the enhancement by UME of transendothelial migration of stem cells as observed by the inventors.

With returning reference to FIGURE 1, an ultrasound system 30 provides controlled ultrasonic energy to external ultrasonic transducers 32 disposed on the subject 10 or to internal ultrasonic transducers 34 delivered inside the subject 10 by a suitable interventional instrument 36 such as a cathether. The ultrasonic transducers 32, 34 are shown diagrammatically in FIGURE 1; in general, the transducers can be concentric electrode arrangements for focused ultrasonic delivery, arcuate electrode arrangements for ultrasonic imaging, tranducer arrays, or so forth. Optionally, the ultrasound system 30 may be configured to perform ultrasound imaging, and toward that end the illustrated ultrasound system 30 includes a display 40 for displaying acquired ultrasound images. The ultrasound system 30 further includes an illustrated keyboard 42 or other user input device to enable a radiologist, physician, or other user to control lthe ultrasound system 30.

For stem cell therapy, a therapy controller 44 controls the intravascular delivery controller 20 and the ultrasound system 30 to perform UME assisted targeted delivery of stem cells to an organ or tissue of interest. A contrast thresholder 46 optionally triggers the UME when the microbubble concentration in the tissue or organ of interest (or in the vasculature thereof) rises above a selected threshold or other selected criterion. Alternatively, the UME can be started a preselected time interval after intravascular injection of the microbubbles is initiated. The therapy controller 44 and contrast thresholder 46 can be variously embodied, for example as software executing on a processor of the ultrasound system 30, software executing on a general-purpose laptop or desktop computer, or so forth.

With continuing reference to FIGURE 1 and with further reference to FIGURE 2, in one suitable therapy process the therapy controller 44 controls the intravascular delivery controller 20 to initiate intravascular introduction of the ultrasonic contrast agent with microbubbles 16 in a starting operation 50. The therapy controller 44 controls the ultrasound system 30 to monitor influx of the microbubbles into the targeted organ or tissue of interest using ultrasonic imaging 52. Additionally or alternatively, another imaging modality can be used for the imaging, such as magnetic resonance imaging (MRI). For monitoring of the influx using MRI, the microbubbles are suitably tagged with a magnetic contrast agent having a magnetic susceptibility detectable by MRI in the subject 10. The contrast thresholder 46 performs a triggering operation 54 and provides a signal when the concentration of microbubbles in the organ or tissue of interest rises above a selected threshold or other selected criterion.

When the contrast thresholder 46 provides the signal, the therapy controller 44 controls the ultrasound system 30 to inject ultrasonic energy focused onto the organ or tissue of interest so as to agitate the microbubbles to produce the UME effect in the vasculature of the organ or tissue of interest in an agitation operation 56. The therapy controller 44 also controls the intravascular delivery controller 20 to stop the intravascular delivery of microbubbles in an operation 58 which may be performed immediately after the contrast thresholder 46 provides the UME initiation signal, or sometime thereafter. In some embodiments, the intravascular delivery of microbubbles continues throughout the agitation operation 56. Depending upon the capabilities of the ultrasound system 30, the ultrasonic imaging may continue during the agitation operation 56, for example by temporally interleaving ultrasound imaging and UME agitation operations. If the imaging 52 employs MRI or another modality, or a second ultrasound system is available, then imaging may be performed simultaneously with the local ultrasonic agitation.

In the embodiment of FIGURE 2, the stem cells serum 14 is not intravascularly delivered until after the agitation operation 56 is completed. Optionally, a delay 60 is interposed between termination of the agitation operation 56 and initiation of intravascular stem cell serum delivery. After the optional delay 60, the therapy controller 44 controls the intravascular delivery controller 20 to initiate intravascular delivery of the stem cells serum 14 in a stem cells delivery operation 64. In some embodiments, the delay 60 is about 15 minutes, so that delivery of the stem cells approximately coincides with the peak of the in pro-inflammatory cytokine levels which occurs about 15 minutes after the UME agitation. Longer or shorter delays are also contemplated, and the delay 60 is optionally omitted entirely. Since the UME effect is believed to heal within about 24 hours, a delay of longer than a few hours is generally not expected to be beneficial. The stem cells delivery 64 may be terminated after a preselected time interval, or may be terminated responsive to a suitable monitoring feedback signal. For example, if the stem cells serum 14 is magnetically tagged, then optional MRI imaging 66 can be used to track the accumulating concentration of stem cells in the organ or tissue of interest, and the stem cells delivery 64 is suitably terminated when the monitoring 66 indicates a desired stem cell concentration has been achieved.

By terminating the local ultrasonic agitating before intravascularly introducing the stem cells, it is assured that the stem cells do not experience the ultrasonic energy used in the UME. This is believed to be advantageous because the ultrasonic energy input of the agitation operation 56 may be sufficiently high to damage the stem cells. The time delay 60, such as a 15 minute delay, is believed to have the additional advantage of allowing the inflammatory effect or other transendothelial cell migration-enhancing process to mature so as to maximally enhance the transendothelial migration of the subsequently introduced stem cells. The general approach of stressing the vasculature in the organ or tissue of interest, followed by a delay to allow the stress to mature, followed by intravascular introduction of stem cells, may also be employed in conjunction with a vasculature stress other than UME. For example, it is contemplated to replace the UME with targeted mechanical, thermal, or chemical stressing of the vasculature in the vicinity of the targeted organ or tissue of interest.

Although the delay 60 is believed to be beneficial, in other embodiments no such delay is included.

With continuing reference to FIGURE 1 and with further reference to FIGURE 3, in another therapy process the therapy controller 44 controls the intravascular delivery controller 20 to initiate simultaneous intravascular introduction of both the ultrasonic contrast agent with microbubbles 16 and the stem cells serum 14 in a starting operation 70. The therapy controller 44 controls the ultrasound system 30 to monitor influx of the microbubbles into the targeted organ or tissue of interest using ultrasonic, magnetic resonance imaging (MRI), or other imaging 72. The contrast thresholder 46 performs a triggering operation 74 and provides a signal when the concentration of microbubbles in the organ or tissue of interest rises above a selected threshold or other selected criterion. When the contrast thresholder 46 provides the signal, the therapy controller 44 controls the ultrasound system 30 to inject ultrasonic energy focused onto the organ or tissue of interest so as to agitate the microbubbles to produce the UME effect in the vasculature of the organ or tissue of interest in an agitation operation 76. The therapy controller 44 also controls the intravascular delivery controller 20 to stop the simultaneous intravascular delivery of microbubbles and stem cells in an operation 78 which may be performed immediately after the contrast thresholder 46 provides the UME initiation signal, or sometime thereafter. In some embodiments, the intravascular delivery of microbubbles continues throughout the agitation operation 76.

In one suitable embodiment of the stem cell delivery system provided herein as an example, the ultrasound therapy transducer comprises eight annular rings with a diameter of eight centimeters, a focal length of eight centimeters (f-number =1), and a center frequency of 1.2 MHz. This transducer is suitably excited by a drive system providing pulsed-wave delivery. Experiments indicate that by choosing the excitation applied to this transducer to be an extended single waveform excitation, it is possible to disrupt the vasculature to improve permeability. The eight-ring transducer is positioned so that the region to be treated is at the focus of the transducer. The transducer can either be mechanically moved over the region to be treated, or the focus can be electronically steered over the region to be treated. Microbubbles are injected and observed to come into the field of view by ultrasonic imaging. The eight-ring therapy transducer is then activated to apply the UME energy (center freq=1.2 MHz, amplitude greater than or about 2 MPa, single pulse). Immediately after the UME agitation is terminated, the stem cells are administered by a suitable intravascular delivery system employing a catheter, needle, or the like.

UME mediated targeted stem cell delivery as disclosed herein has been performed in vivo by the inventors, using rats as test subjects. Human mesenchymal stem cells (MSCs) were isolated from hip bone marrow, diluted with Ca²⁺- and Mg²⁺-free phosphate -buffered saline (PBS), filtered, laid over 15 ml Ficoll-Paque™ Plus (available from Amersham Pharmacia Biotech, Uppsala, Sweden) and centrifuged. Mononuclear cells were isolated and maintained as monolayers in 10 ml growth medium α-MEM supplemented with 2 mg/ml L-glutamine, 50 U/ml penicillin, 50 μg/ml streptomycin and 20% (v/v) of a selected batch of fetal calf serum (all chemicals were obtained from Gibco BRL, Karlsruhe, Germany). Non-adherent cells were removed after 2 days at 37°C in a humidified 5% CO₂ atmosphere. In some subjects the UME target zone was set in the anterior Ie ft- ventricular wall in non-ischemic myocardium, while in other subjects UME was aimed at the anteroseptal peri-infarction borderzone. An ultrasound system from Philips Research North America, Briarcliff Manor, NY, USA was used to provide b-mode high-resolution ultrasound imaging at a frequency of about 15 MHz so as to image anatomical structures. For the UME, low- frequency (about 1.2 MHz) high-energy focused ultrasound energy was applied. The ultrasonic transducers incorporated an acoustic coupler designed for small animals and filled with degassed water, and was mounted on a stepper-motor stage which allowed movement of the treatment zone in three dimensions. Reatime guidance using b-mode imaging allowed precise and interactive positioning of the focal zone of the UME focused ultrasound energy into a selected segment of myocardium. The UME focal zone of the treatment ultrasound transducer was about 1 mm in diameter and 6 mm in length. To create a larger treatment zone (about 30 cm), spatial coordinates obtained from the realtime b-mode imaging were used in driving the motor stage and generating the ultrasound pulses so as to scan the focal zone.

SonoVue™ (available from Bracco Inc., Milano, Italy) was infused into a femoral vein cannulated with a PE-50 tube at approx. 100 μl/minute. The microbubble agent was agitated continuously during injection using a syringe pump. Flow rate was adjusted to achieve suitable left-ventricular opacification without shadowing. Steady state conditions were achieved about two minutes after start of the SonoVue™ infusion. The scanning of the UME ultrasound focus was performed so as to ensure uniform delivery of ultrasound-pulses across the target zone during the a selected phase of the cardiac cycle and to ensure sufficient replenishment time for fresh microbubbles following localized destruction of microbubbles by the UME agitation. Pulses were applied at a 0.2 Hz rate, and each pulse consisted of a sinusoidal excitation with the following parameters: 1.2 MHz; 10.000 cycles; 4.4 MPa peak negative pressure. In total the target zone of each heart received a sequence of 30 spatially distributed pulses repeated twice.

The invention has been described with reference to the preferred embodiments. Modifications and alterations may occur to others upon reading and understanding the preceding detailed description. It is intended that the invention be construed as including all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims

CLAIMSHaving thus described the preferred embodiments, the invention is now claimed to be:

1. A method of delivering cell-sized objects to a targeted organ or tissue of interest, the method comprising: introducing (64, 70) the cell-sized objects into the bloodstream; introducing (50, 70) microbubbles into the bloodstream; and locally agitating (56, 76) the introduced microbubbles, the agitating being substantially localized to the targeted organ or tissue of interest, the local agitating of the introduced microbubbles enhancing transendothelial migration of the cell- sized objects into the targeted organ or tissue of interest.

2. The method of claim 1, wherein the local agitating (56, 76) comprises: generating ultrasonic energy focused on the targeted organ or tissue of interest.

3. The method of claim 2, wherein the cell-sized objects include stem cells, and the local agitating (56, 76) of the introduced microbubbles enhances transendothelial migration of the stem cells into the targeted organ or tissue of interest.

4. The method of claim 2, wherein the local agitating (56, 76) further comprises: mechanically or electronically moving a focus of the ultrasonic energy across the targeted organ or tissue of interest.

5. The method of claim 2, wherein the introducing of microbubbles (50, 70) into the bloodstream comprises introducing an ultrasonic contrast agent including said microbubbles into the bloodstream, and the method further comprises: ultrasonically imaging (52, 72) the ultrasonic contrast agent including said microbubbles in the bloodstream in the targeted organ or tissue of interest.

6. The method of claim 1, wherein the introducing of microbubbles (50, 70) into the bloodstream comprises: introducing a gaseous precursor into the bloodstream; and converting the gaseous precursor in the bloodstream into said microbubbles by application of ultrasonic energy.

7. The method of claim 1, wherein the introducing of the cell-sized objects (64, 70) into the bloodstream and the introducing of the microbubbles (50, 70) into the bloodstream both employ a same intravascular injection pathway (22).

8. The method of claim 1, wherein the introduced microbubbles have sizes between about one-half micron and about twenty microns.

9. The method of claim 1, further comprising completing the agitating (56) before starting the introducing of the cell-sized objects (64) into the bloodstream.

10. The method of claim 1, wherein the introducing of microbubbles (50) into the bloodstream and the agitating (56) both precede in time the introducing of the cell-sized objects (64) into the bloodstream, and the method further comprises: delaying a finite non-zero delay interval (60) between completion of the agitating (56) and the introducing of the cell-sized objects (64) into the bloodstream.

11. An apparatus including an ultrasound system (30), an intravascular delivery system (20, 22, 24), and a therapy controller (44, 46) configured to perform the method of claim 1.

12. An apparatus for delivering cell-sized objects to a targeted organ or tissue of interest, the apparatus comprising: an intravascular delivery device (20, 22, 24) configured to deliver the cell-sized objects and microbubbles into the bloodstream; an ultrasound system (30, 32, 34, 36); and a therapy controller (44) configured to control the intravascular delivery system to control delivery of the cell-sized objects and the microbubbles into the bloodstream and to control the ultrasound system to ultrasonically agitate intravascular microbubbles in the targeted organ or tissue of interest so as to enhance transendothelial migration of the cell-sized objects into the targeted organ or tissue of interest.

13. The apparatus of claim 12, wherein the ultrasound system (30, 32, 34, 36) is configured to ultrasonically image at a first frequency and to ultrasonically agitate at a second frequency lower than the first frequency.

14. The apparatus of claim 12, further comprising: an imaging system selected from the group consisting of (i) said ultrasound system (30, 32, 34, 36) and (ii) an imaging device other than said ultrasound device, the imaging system configured to detect intravascular microbubbles in the targeted organ or tissue of interest; and a contrast thresholder (46) communicating with the therapy controller (44) to initiate ultrasonic agitation of intravascular microbubbles in the targeted organ or tissue of interest responsive to the imaging system detecting a threshold concentration of intravascular microbubbles in the targeted organ or tissue of interest.

15. The apparatus of claim 12, wherein the ultrasound system (30, 32, 34, 36) comprises at least one of: an ultrasonic transducer (32) disposed on a subject (10) including said targeted organ or tissue of interest, and an ultrasonic transducer (34) configured to be delivered using an interventional instrument (36) into a subject ultrasound system (10) including said targeted organ or tissue of interest.

16. The apparatus of claim 12, wherein the intravascular delivery device (20, 22, 24) is configured to deliver the cell-sized objects comprising stem cells into the bloodstream, and therapy controller (44) is configured to terminate the ultrasonic agitation and then to control the intravascular delivery system to start delivery of the stem cells into the bloodstream after termination of the ultrasonic agitation.

17. The apparatus of claim 12, wherein the intravascular delivery device (20, 22, 24) is configured to deliver microbubbles into the bloodstream by delivering a gaseous precursor into the bloodstream, said gaseous precursor delivered into the blood stream being converted to microbubbles in the bloodstream.

18. A method of delivering cell-sized objects to a targeted organ or tissue of interest, the method comprising: performing a transendothelial migration-enhancing process (56, 76) on vasculature of the targeted organ or tissue of interest; and introducing (64, 70) the cell-sized objects into the bloodstream, the cell-sized objects preferentially undergoing transendothelial migration out of the vasculature of the targeted organ or tissue of interest due to the transendothelial migration-enhancing process.

19. The method as set forth in claim 18, wherein the cell-sized objects include stem cells, the stem cells are introduced (64) into the bloodstream after the transendothelial migration-enhancing process (56) is performed, and the method further comprises: delaying a preselected delay time (60) between the performing and the introducing.

20. The method as set forth in claim 19, wherein the performing of a transendothelial migration-enhancing process (56, 76) comprises: ultrasonically agitating (56, 76) microbubbles in the vasculature of the targeted organ or tissue of interest.