Patent Grant
10065018
The present invention is directed to apparatus and methods for promoting tissue perfusion in the vascular territory served by vessels occluded by severe atherosclerosis by delivering biologics into a subintimal space, and/or by delivering biologics from the subintimal space into tissue surrounding the vessel.
Peripheral arterial disease (PAD) is a highly prevalent disease affecting over 12 million people in the United States (Golomb et al., Circulation, 2006). As PAD progresses, atherosclerosis and chronic inflammation can result in markedly reduced blood flow to the legs, feet, and hands. Critical limb ischemia (CLI) is the most advanced stage of PAD, and affects more than 500,000 people annually, causing rest pain in the foot, non-healing ulcers, delayed wound healing, limb/digital gangrene, and may eventually lead to amputation.
Conventional treatment for severe arterial occlusive disease includes bypassing or crossing the occlusions using endovascular techniques such as angioplasty, atherectomy, and/or stents. However, many patients with severe, diffuse arterial occlusive disease, as is typically seen in CLI, are either not ideal candidates for an endovascular approach to percutaneous revascularization due to their significant co-morbidities (i.e. renal dysfunction, myocardial dysfunction) or significant functional or nutritional debilitation. Moreover, when arterial occlusions are extensive and severely calcified, which is the typical in CLI patients with femoropopliteal and infrapopliteal occlusive disease, interventional attempts to re-establish vessel patency to improve tissue perfusion are frequency sub-optimal or unsuccessful due to inability to traverse these complex, long arterial occlusions. Given this technical failure to re-establish tissue perfusion, amputation is frequently required as a life saving measure, resulting in long-term disability, a diminished quality of life and substantial expenditures to the health care system.
In recent years, stem cell therapies have been investigated as providing a possible adjunct or alternative for patients who are either “poor option” or “no option” candidates for a percutaneous interventional procedures due to extent of their occlusive disease. Stem cells are pluripotent cells with the ability to self-renew and differentiate. The therapeutic effect of stem cells to improve perfusion to ischemic tissues was first observed when administrating bone marrow cells into a mouse model of hind-limb ischemia. (Asahara et al., Circ. Res., 1999). In 2002, autologous bone marrow mononuclear cells were observed to exhibit therapeutic angiogenesis when being injected to a human patient with ischemic limbs due to PAD. (Tateishi-Yuyama et al., Lancet, 2002). While the cellular mechanism(s) behind the therapeutic effect of stem cells is still under investigation, current studies indicate that stem cells promote neo-vascularization by angiogenesis, vasculogenesis, arteriogenesis, or a combination of the three.
Stem cells are conventionally delivered via systemic infusion (i.e., intravenous or intra-arterial) or local injection near areas of ischemic tissue. These delivery methods have remained in use, and relatively static, for over a decade, and may significantly hamper the effectiveness of stem-cell therapy. Specifically, stem cell viability and retention rates after conventional delivery methods are extremely low, typically less than 10% of the injected number. To compensate for the cell loss, a much higher volume of stem cells is needed to elicit a therapeutic response. (Behfar, et al., Circ Cardiovasc Interv, 2013). However, simply injecting a larger number of stem cells cannot compensate for inefficient delivery modalities. Furthermore, stem cells have relatively large diameters and may occlude vessels, compromising their therapeutic effect and potentially contributing to worsening ischemic symptoms. (Perin et al., J Mol Cell Cardiol, 2008).
The suboptimal performance observed with conventional stem cell delivery modalities has multiple causes. First, stem cells differ from traditional therapeutics in that the cells are fragile and extremely sensitive to their microenvironments. Previously known delivery methods deposit the stem cells directly at the occlusion sites, where—due to ischemia, hypoxia, oxidative stress, or inflammation—the microenvironment may be harsh, and contribute to massive cell apoptosis. (Kurtz, et al., Int J Stem Cells, 2008; Li, et. al. Stem Cells, 2007). Further, the cell injection process may itself contribute to poor cell viability, as injection may cause mechanical disruption to the stem cells, e.g., barotrauma caused by fluid sheer and extreme pressure fluctuations. Moreover, in certain applications, such as delivery of stem cells to long femoropopliteal occlusions, the migration of stem cells to ischemic areas may be impeded by the long, calcified occlusions. Alternatively, such stem cells may be easily washed out of the delivery area or entrapped in organs if taken up by systemic circulation.
In view of the foregoing drawbacks of previously known stem cell delivery methods and apparatus, there exists a need for safe and efficacious administration of biologics, such as stem cells, to occluded vessels and ischemic tissue to promote angiogenesis, especially in patients with severely ischemic tissues. In particular, it would be advantageous to provide methods and apparatus for delivering stem cells to ischemic tissue that overcome previously known methods requiring massive direct injections with low migration or uptake, or delivery of stem cells into open arteries in the vicinity of an ischemic tissue, which results in low viability and wash out.
It therefore would be advantageous to provide methods and apparatus for delivering stem cell therapy to patients with severely ischemic tissues, wherein such methods and apparatus enhance cell viability and retention rates, and promote the overall therapeutic effect of stem cells.
It further would be desirable to provide apparatus and methods dedicated to deliver stem cells and other biologics to occluded vessels of a patient in a safe and efficient manner, such that the stem cells may be delivered to the vicinity of an occluded vessel in a protected manner that enhances cell viability and retention, and reduces the risk of wash-out and entry of such cells into systemic circulation.
It also would be desirable to provide apparatus and methods to deliver stem cells such that the stem cells are delivered into a protected environment with reduced mechanical disruption, thereby promoting stem cell viability.
It further would be desirable to provide apparatus and methods for delivering biologics to promote angiogenesis in ischemic tissue that provides uniform distribution of the biologics along a designated region.
It still further would be desirable to provide apparatus and methods suitable for delivering a metered amount of stem cells to the vicinity of an occluded vessel to promote angiogenesis.
In view of the aforementioned drawbacks of previously known stem cell delivery methods and apparatus, the present invention provides apparatus and methods for delivering biologics, such as stem cells, to a subintimal space of an occluded vessel of a patient body. In accordance with one aspect of the invention, a subintimal space is created between the medial and adventitial layers of an occluded vessel, which is expected to provide a more hospitable, protected microenvironment for the cells, thereby improving uptake into the surrounding ischemic tissue and reducing wash-out and the risk that such stems cells will be carried into systemic circulation.
Apparatus and methods are provided for delivering biologics therapies that advantageously are expected to reduce the amount of biologics needed to elicit a therapeutic response. Delivery of biologics, such as stem cells, into a supported subintimal space also is expected to reduce the potential for mechanical disruption to the biologics and improve cell viability. In addition, apparatus and methods in accordance with the present invention are expected to provide a more uniformed distribution of a metered amount of stem cells within a designated region, thereby reducing the required amount of biologics to be deposited and reducing procedural cost.
In accordance with one aspect of the present invention, a biologics delivery device is provided for creating and maintaining a subintimal space in an occluded blood vessel of a patient and for delivering a biologic into the subintimal space. The biologics delivery device comprises a catheter having a proximal end, a distal region having a distal end, a lumen extending there between, and a plurality of through-wall apertures distributed along the distal region. The plurality of through-wall apertures is in fluid communication with the proximal end and the lumen. The biologics delivery device preferably further comprises an expandable member disposed in the distal region, which is configured to transition between a collapsed state, suitable for insertion into the subintimal space, and an expanded state for delivery of biologics. During delivery of biologics, the expandable member is radially expanded to contact the walls of the subintimal space to support the space patent.
The biologics delivery device also may include an actuator for transitioning the expandable member between the collapsed state and the expanded state. The actuator also may retain the expandable member in the expanded state during biologics delivery. The actuator may be constructed to include a sheath configured to constrain the expandable member in the collapsed state. In some embodiments, the actuator may comprise a cuff disposed proximal or distal to and coupled to the expandable member, such that the expandable member may be expanded by pushing, pulling, twisting the cuff, or a combination of such motions.
In accordance with one aspect of the present invention, the plurality of through-wall apertures are radiused to reduce the risk of mechanical damage to the biologics during delivery. The plurality of through-wall apertures further preferably are sized to provide substantially uniform distribution of the biologics along the distal region of the biologics delivery device. In some embodiments, the diameters of the plurality of through-wall apertures may gradually increase in the proximal to distal direction. In some embodiments, the plurality of through-wall apertures are directed towards the adventitial layer.
The biologics delivery device further may comprise at least one radiopaque marker for tracking the location of the device under fluoroscopic visualization.
A method of using the biologics delivery device for promoting angiogenesis in an ischemic area of a patient also is provided, wherein the biologics delivery device is introduced into a previously created subintimal space. An expandable member disposed on the device is radially expanded to contact and support the surface of the subintimal space. While the expandable member is retained in the expanded state to support the subintimal space, the biologics are substantially uniformly distributed into the subintimal space through the plurality of through-wall apertures disposed along the distal region. In addition, a contrast agent may be administered with the delivery of the biologics, so that migration of the biologics out of the subintimal space and into the surrounding ischemic tissue may be observed under fluoroscopy.
In accordance with another aspect of the disclosure, a biologics delivery device is introduced into the subintimal space created between the medial and adventitial layers of an occluded vessel, and is configured to deposit biologics from the subintimal space to tissue surrounding the occluded vessel, such as skeletal muscle surrounding the vessels of a lower limb, thereby enhancing biologics survival and reducing the risk of systemic washout.
The biologics delivery device for delivering a biologic to tissue surrounding an occluded blood vessel of a patient includes a catheter having a proximal end, a distal region having a distal end, and a side wall defining a catheter lumen; an expandable member disposed in the distal region, which is configured to support a subintimal space in an occluded blood vessel of a patient, and to transition between a collapsed state and an expanded state; and a hollow needle having a penetration tip deployable from inside the catheter lumen to outside the catheter lumen, and into the tissue. The expandable member in the expanded state allows the flow of oxygenated blood to the occluded blood vessel.
The biologics delivery device also may include a side opening formed through the side wall and disposed on the distal region, wherein the hollow needle is deployed through the side opening. The catheter lumen also may terminate at the side opening.
The biologics delivery device further may include an actuator for transitioning the expandable member between the collapsed state and the expanded state. The actuator may further be configured to maintain the expandable member in the expanded state during the delivery of the biologic.
In accordance with another aspect of the present disclosure, the hollow needle is configured to be advanced through the expandable member in the expanded state. The hollow needle may be formed of nitinol. The expandable member may include a plurality of strands. The expandable member may also include a mesh-like structure.
In accordance with another aspect of the present disclosure, the biologics delivery device may include at least one radiopaque marker.
The biologic may include one or more hematopoietic stem cells, endothelial progenitor cells, mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, growth factors, or any combination thereof.
A method of using the biologics delivery device for promoting angiogenesis in an ischemic area of a patient also is provided, wherein the biologics delivery device is introduced into a previously created subintimal space between an adventitial layer and an intimal layer of a vascular wall of an occluded blood vessel, the subintimal space having a surface. The distal end of the biologics delivery device is introduced into the subintimal space, the expandable member in the subintimal space is transitioned to an expanded state to contact and support the surface of the subintimal space. The penetration tip of the hollow needle is deployed from inside the catheter lumen to outside the catheter lumen, and into the tissue surrounding the occluded blood vessel. A biologic through the biologics delivery lumen extending through the hollow needle is delivered to the tissue. In addition, a contrast agent may be administered with the delivery of the biologics, so that migration of the biologics out of the subintimal space and into the surrounding ischemic tissue may be observed under fluoroscopy.
Arteries and veins generally are comprised of three layers: the innermost layer called the intimal layer, the outermost layer called the adventitial layer, and the medial layer located in between the intimal and the adventitial layers. The intimal and medial layers are readily separated from the adventitial layer. For example, it is known that when attempting to pass an occlusion with a guidewire, the guidewire may sometimes inadvertently penetrate the subintimal space between the intimal and the adventitial layer. Hereinafter, in the context of this specification, the term “intimal layer” refers to the intima/media that adjoins the occluded vessel lumen, while the term “adventitial layer” refers to the outer layer of the vessel that may be separated from the intimal layer when a subintimal space is created.
Referring to
Biologics delivery device 100 preferably has a length and diameter suitable for use in the desired peripheral vessel, e.g., 70 cm to 150 cm in length, with a diameter from 2.5 mm to 60 mm. Distal region 107 preferably has a length of about 1 cm to 5 cm. Catheter shaft 101 may be formed of conventional materials of construction, e.g., a plastic material such as polyethylene, polyvinylchloride, polyesters or the like.
Referring to
As depicted in
Still referring to
Referring now to
As for the embodiment of
Biologics lumen 410 is disposed adjacent to guidewire lumen 411 and is in fluid communication with apertures 401-409. The size and positioning of biologics lumen 410 preferably are selected to reduce biologics residue in the catheter shaft at the conclusion of the delivery, which also permits a more accurate measurement of amount of biologics delivered. In accordance with one aspect of the present invention, it is expected that depositing a biologic such as stem cells within the subintimal space will facilitate uptake into ischemic tissue, and promote angiogenesis in the following ways: First, depositing the biologic in the subintimal space will reduce the risk that blood flow in the vessel will cause wash-out of the biologic and reduce the amount that is carried into systemic circulation. Second, the subintimal space provides a more protective environment for the biologic. Third, by depositing the biologic directly into the subintimal space, uptake of the biologic will not be impeded by the presence of thrombus or calcifications as would be the case if the biologic were to be deposited into a tunnel formed with thrombus located in the vessel. Fourth, because the biologic is delivered directly into a healthier subintimal tissue environment than if delivered within the vessel proper, the biologic is expected to be much more likely to obtain necessary nutrition from the surrounding tissue, thereby enhances survival. Fifth, because delivering the biologic into the subintimal space reduces the risk of washout, smaller amounts of biologic may be used than would otherwise be possible, thereby reducing the material costs of such a procedure. Sixth, a nutrient matrix may be administered in combination with the biologic into the subintimal space, thereby further improving biologic viability.
Referring to
With respect to
The distal region in accordance with the principles of the present invention preferably has a length of 1.0 cm to 5.0 cm and may be tapered to facilitate delivery. The expandable member may be permanently coupled to the catheter shaft or may be manufactured as a separate piece and coupled to the device prior to use.
Referring to
The lumen defining the subintimal space may subsequently be dilated using a balloon angioplasty catheter, atherectomy device, by stenting, or other known techniques. As shown in
Biologics delivery device 900 may comprise one or more radiopaque markers to assist placement of the device under fluoroscopic visualization, and to confirm dilation of the subintimal space prior to and during biologics delivery.
A metered amount of prepared biologics solution or suspension may be infused into the biologics lumen from a reservoir and deposited towards adventitia A through a plurality of through-wall apertures 903 disposed along the distal region of biologics delivery device 900. Biologics preferably are injected in a solution or suspension, a hydrogel, or in a microsphere formulation that buffers the biologics during delivery and reduces mechanical damage. A fluid flow controller may be provided to meter fluid flow from the reservoir into the biologics lumen at a selected fluid pressure. The fluid or suspension used to deliver the biologics also may include a contrast agent to assist in visualizing delivery of the biologics into the subintimal space, and subsequent uptake into the surrounding tissue. Optionally, the biologics lumen is flushed with saline or other suitable fluid to reduce biologics residue in the biologics lumen.
The biologic may be fluorescently labeled and tracked using scintigraphy, PET, or MRI. The expandable member preferably is maintained in the expanded state for a predetermined period to facilitate migration of the stem cells into the adventitial layer before the device is re-collapsed and withdrawn. The expandable member preferably is configured to re-collapse sufficiently slowly to avoid damaging the deposited biologics.
In accordance with one aspect of the present invention, stem cells used in conjunction with the apparatus and method described herein above may be collected from a number of allogeneic and autologous sources.
A mixed population of various types of undifferentiated cells may be collected from a patient's bone marrow, including hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs). HSCs are stem cells that form blood and immune cells and can be readily isolated from bone marrow, umbilical cord blood, or after mobilization into peripheral blood. MSCs are another type of adult bone marrow derived stem cells with the ability to form cartilage, bone, adipose tissue, and marrow stroma, and are capable of sustained expression of growth factors. MSCs also may be isolated from adipose tissue, the umbilical cord, fetal liver, muscle, and lung, and can be successfully expanded in vitro. Endothelial progenitor cells are primitive bone marrow cells that also are reported to possess the ability to mature into cells that form vessel walls. (Luttun et al., Trends Cardiovasc Med. 2002.) In addition to bone marrow stem cells, embryonic stem (ES) cells are capable of unlimited self-renewal while maintaining the potential to differentiate into almost all cell lineages. The ethical issues related to ES cells promoted the development of induced pluripotent stem (iPS) cells, which share many properties with ES cells without the ethical concerns. Additionally, the stem cells may be combined with growth factors such as EGF, FGF, GDF, IGF, PDGF, and VEGF to promote cell differentiation.
The present disclosure also provides apparatus and methods for delivering biologics, such as stem cells, from a subintimal space of an occluded vessel of a patient body to tissue surrounding the occluded vessel.
In accordance with one aspect of the present disclosure, biologics may be delivered from the subintimal space to tissue surrounding the vessel. In a non-limiting example, where the occluded vessel is located in the lower limb of a patient, tissue surrounding the occluded vessel may be skeletal muscle. Tissue surrounding the occluded arteries may receive blood supply from other vessels, and therefore may be viable and less hypoxic comparing to the occluded vessel. Depositing the biologics into such a friendlier environment is expected to enhance biologics survival, and reduce the risk of systemic washout.
Referring now to
Still referring to
Elongated catheter shaft 1005 may include additional components to facilitate the positioning and deployment of needle 1003. As seen in
Expandable member 1001 preferably maintains in the expanded state during delivery of the biologics, and needle 1003 preferably extends through the mesh opening of expandable member 1001. In accordance with one aspect of the present disclosure, expanding the subintimal space while delivering the biologics may allow for the introduction of oxygenated blood into the vicinity of tissue T, which is expected to further promote the viability of the deposited biologics.
In accordance with another aspect of the present disclosure, the beveled tip of needle 1300 may include at least one radiopaque marker. Additionally, elongated catheter shaft 1005 further may comprise at least one radiopaque marker. The radiopaque markers may be configured to track the location of the device, and/or deployment of needle 1003 into tissue T under fluoroscopic visualization. Additionally, and/or alternatively, the proximal end of device 1000 may include at least one fiduciary mark indicating the deployment of needle 1003.
Biologics delivery device 1000 also may include a plurality of apertures disposed on elongated catheter shaft 1005, and may be configured to deposit biologics into both the subintimal space and tissue T surrounding the occluded blood vessel.
Those skilled in the art will appreciate that the invention can be practiced in other than the described embodiments, which are presented for purposes of illustration and not of limitation.
This application is a continuation-in-part application of U.S. patent application Ser. No. 15/072,249, filed Mar. 16, 2016, the entire contents of which are incorporated herein by reference.
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| Child | 15268069 | US |
