Patent Application
20190076371
This invention relates generally to the production and use of microrobot structures and, more particularly, to magnetically driven microrobots configured to carry and deliver cells to desired sites.
Microrobots have been the subject of recent attention in light of their potential to revolutionize many aspects of medicine and their potential to enable new procedures never before possible. Microrobots might, for example, be used for the localized delivery of chemical and biological substances (e.g., pharmacotherapy agents, living tissue, etc.), to remove material (e.g., neoplastic tissue, osteophytes, etc.) by mechanical means, to act as simple static structures (e.g., stents, occlusions, implants, etc.), or to transmit information from a location within the body (e.g., a location from which it would otherwise be very difficult to obtain information).
Various configurations of microrobots have been developed for use in minimally invasive medical techniques which make some existing therapeutic and diagnostic procedures less invasive. However, the minimally invasive surgery used to introduce such microrobots into the patient's body is nevertheless invasive and requires an incision of some size with the aid of a mechanical instrument. Such open surgery may lead to infection and injury during the insertion.
Moreover, existing microrobots configured for carrying living tissue in the form of individual cells typically have a very limited cell load capacity and/or provide very limited transport ability. For example, S. Tottori, L. Zhang, F. Qiu, K. K. Krawczyk, A. Franco-Obregón, B. J. Nelson, “Magnetic helical micromachines: fabrication, controlled swimming, and cargo transport,” Advanced materials 24, 811-816 (2012) and S. Tottori, L. Zhang, F. Qiu, K. K. Krawczyk, A. Franco-Obregón, B. J. Nelson, “Magnetic helical micromachines: fabrication, controlled swimming, and cargo transport,” Advanced materials 24, 811-816 (2012), the disclosures of which are hereby incorporated herein by reference, discuss helical magnetic swimming micromachines with a microholder and a U-shaped magnetic microrobot, respectively, each of which can only transport a single cell with very limited transport ability. S. Kim, F. Qiu, S. Kim, A. Ghanbari, C. Moon, L. Zhang, B. J. Nelson, H. Choi, “Fabrication and characterization of magnetic microrobots for three-dimensional cell culture and targeted transportation,” Advanced Materials 25, 5863-5868 (2013), the disclosure of which is hereby incorporated herein by reference, discusses microrobots having a structure supporting very limited cell load capacity.
Patent documents US20090098183A1, WO2005095581A1, WO1988003785A1, and WO2012149358A1, the disclosures of which are hereby incorporated herein by reference, describe a scaffold-like 3D structure for implanting to repair damage tissue or organ that provides very limited cell load capacity and that does not provide magnetic actuation ability and cannot be used for magnetic driven cell transportation in body. Patent documents U.S. Pat. No. 8,900,293 and U.S. Pat. No. 7,846,201, the disclosures of which are hereby incorporated herein by reference, discuss paramagnetic particles associated with a therapeutic agent, drug, and/or a cell to be delivered to a targeted location, wherein the paramagnetic particles provide a relatively low magnetization under applicable external magnetic fields, thus resulting in very limited transport ability. Patent document US20130017229, the disclosure of which is hereby incorporated herein by reference, discusses a magnetic porous scaffold in centimeter size, which can act as a depot of various cells, and the cell release can be controlled by external magnetic fields, wherein the porous scaffold structure is difficult to be used in vivo and thus is impractical for providing cell transport ability with respect to living tissue applications. Patent document US20110270434, the disclosure of which is incorporated herein by reference, discusses magnetic nanostructured propellers to detect biomolecules that work for the controlled transportation of molecules and the delivery of microscopic and nanoscale objects to targeted cell, wherein such nanostructured propellers cannot be used for carrying and delivering cells. Patent document US20120253102, the disclosure of which is hereby incorporated herein by reference, discusses superparamagnetic microspheres label cells to enhance cell retention, engraftment, and functional benefit, wherein the microspheres are not designed to transport the cells in vivo. Patent documents US20140302110 and US20150351897A1, the disclosures of which are incorporated herein by reference, describe magnetic bio-scaffold to transport multiple cells, however the cell load capacity remains very limited.
The present invention is directed to systems and methods which provide magnetically driven biocompatible microrobots comprising a porous body having a magnetic layer and a biocompatible layer configured to carry and deliver cells to desired sites. The porous body of embodiments of a microrobot herein may comprise a polymeric, ceramic, or nanofiber three-dimensional structure. The porous structure of the body may, for example, be configured to mimic the extracellular matrix, in which nutrients can be easily supplied for tissue vascularization to yield functional tissues and organs. The pores in the porous body of embodiments may be sized in correspondence with the type of cells to be carried by the microrobot. The magnetic layer of embodiments may be provided on some portion or all of a surface of the microrobot for configuring the microrobot to be controlled with an external magnetic field, such as to enable the magnetic microrobot to be positioned at a target site without the use of surgery or mechanical instrument. The biocompatible layer of embodiments may be provided on some portion or all of a surface of the microrobot, possibly coating some or all of the aforementioned magnetic layer, for configuring the microrobot for improved biostability and biocompatibility. A microrobot coated with magnetic materials and biocompatible materials according to embodiments herein is thus configured to allow magnetic control of the microrobot and to facilitate cell cultivation on it.
Embodiments of microrobots of the present invention are configured with enhanced cell-loading ability. For example, such embodiments may include a plurality of burr members disposed upon the porous body for configuring the microrobot for enhanced cell-loading. The burr members may, for example, comprise relatively thin protrusions extending generally orthogonally from the surface of the microrobot porous body, wherein the interspacing of the burr members may correspond with the type of cells to be carried by the microrobot. Cells to be carried and/or delivered to desired sites may, for example, each be cultured between adjacent burr members disposed on the outside of a microrobot of embodiments herein. The burr member structure of embodiments herein allows more cells to adhere onto the microrobot, facilitating a higher cell-loading ability for the microrobot.
In operation of embodiments herein, a magnetically driven biocompatible microrobot is used to carry and deliver targeted cells to a desired site, without the use of surgical techniques to deliver the microrobot directly to the desired site. The carried cells can be spontaneously released to the surrounding tissues from a microrobot configured in accordance with the concepts herein when the microrobot arrives at the desired site; as confirmed by in vitro and in vivo experiments. For example, the porous three-dimensional structure of microrobots of embodiments herein, particularly when adapted to include burr members in accordance with concepts herein, have been proven to effectively release cells spontaneously when disposed at a desired site.
It should be appreciated that microrobots configured in accordance with the foregoing embodiments present a great potential for future applications in tissue repair and regeneration in precision medicine. Embodiments of a magnetically driven biocompatible microrobot may be utilized in facilitating new approaches to organ regeneration.
The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present invention.
For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawing, in which:
The concepts described herein provide for the design and fabrication of magnetically driven biocompatible microrobots, such as may be utilized as targeted cells carrying microrobots. For example, functional cells, such as MC3TE-E1 and mesenchymal stem cells (MSCs), can be carried and transferred by the magnetically driven biocompatible microrobots of embodiments of the invention. In operation according to some embodiments, MSCs can be delivered and released because MSCs can potentially differentiate into various cell types of the host tissues, such as adipocytes, chondrocytes, and myocytes. Irrespective of the particular cells for which a magnetically driven biocompatible microrobot may be configured to carry, the microrobots of embodiments of the invention are configured for controlling the movement of microrobot using a magnetic field applied, whereby cells can be carried and released to a localized part of the human body.
Porous body 110 of embodiments of the invention may, for example, comprise a three-dimensional structure in the form of cylinder, a hexahedron, an ellipsoid, a polyhedron, a circular cone, or a sphere, such as may be formed from one or more materials (e.g., polymer, ceramic, nanofiber, etc.). The size and shape of porous body 110, and correspondingly microrobot 100, may vary depending on the type of the cells to be carried and/or delivered, the physiology of the target delivery site, the morphological attributes of an expected path to the target delivery site, etc. In accordance with some embodiments herein, porous body 110 may comprise a three-dimensional structure having dimensions (e.g., diameter, length, width, and/or height) preferably in the range of 1-1000 micrometer, and more preferably in the range of 30-100 micrometer, because microrobots with the foregoing dimensions can readily move within the body such as in vessels, cerebral ventricles, and viscoelastic media and fluid of organs with the help of magnetic field. Moreover, porous body 110 of embodiments may comprise a sphere because a spherical structure may easily fuse with host tissue and thus facilitate cell transfer from the microrobot to the tissues. The porous structure of porous body 110 of the illustrated embodiment is configured to mimic the extracellular matrix to facilitate the supply of nutrients for tissue vascularization to yield functional tissues and organs. Pores 111 of porous body 110 of the illustrated embodiment are sized in correspondence with the type of cells to be carried by microrobot 100. For example, the diameter of the orifice of pores 111 in the outer surface of porous body 110 is sized in correspondence with an average circumference of the particular cells (e.g., the average interphase length or circumference of targeted cells) to be carried by microrobot 100.
It should be appreciated that the porous structure of porous body 110 may itself be utilized to carry cells. For example, cells to be carried and/or delivered to desired sites may each be cultured within an orifice of one of pores 111, thus being disposed between opposing edges of the pore orifice (e.g., through cell adhesion to biocompatible material of microrobot 100). However, microrobot 100 of the illustrated embodiment includes a plurality of burr members 120 utilized to carry cells.
Burr members 120 of embodiments comprise relatively thin protrusions extending generally orthogonally from the outer surface of porous body 110. Each burr member 120 may, for example, comprise a protuberance extending from the outer surface of porous body 110 in the form of a cylinder, a hexahedron, an ellipsoid, or a polyhedron. Burr members 120 of embodiments are adapted so as not to be so long as to injure tissues/organs as the microrobots move in the body and so as to not be so short as to discourage solid cell attachment thereto. Each burr member 120 may, for example, preferably he preferably in the range of 1-30 micrometers, and more preferably from 5-15 micrometers. Moreover, the distal end of burr members 120 of embodiments may be adapted so as to decrease the potential damage to the tissues and organs when these cell-cultured microrobots are delivered to the desired position in the body. For example, burr members 120 of the illustrated embodiment include ball terminal structures at the distal end thereof for minimizing the potential for damage to tissues by the microrobots. The cross section size of burr members 120 may preferably be in the range of 1-10 micrometers, and more preferably from 2-5 micrometers, according to some embodiments. Burr members 120 of the illustrated embodiment are provided with an interspacing corresponding with an average circumference of the particular cells (e.g., the average interphase length or circumference of targeted cells) to be carried by microrobot 100. For example, burr members 120 shown in
Although the illustrated embodiment shows a configuration of microrobot 100 in which both the size of the orifice of pores 111 and the interspacing of burr members 120 correspond to a size of the particular cells to be carried by the microrobot, there is no limitation with respect to both the sizing of the pores and the spacing of the burr members corresponding to a size of cells to be carried. Embodiments of a magnetically driven biocompatible microrobot may, for example, comprise pores having a diameter sized to facilitate the supply of nutrients for tissue vascularization to yield functional tissues and organs without necessarily corresponding to a size of the particular cells to be carried by the microrobot, whereas the burr member interspacing may correspond to the size of the particular cells to be carried by the microrobot
Burr members 120 of the illustrated embodiment of microrobot 100 are disposed upon porous body 110 for configuring the microrobot for enhanced cell-loading. Cells to be carried and/or delivered to desired sites (e.g., cells 101 of
It should be appreciated that, although the foregoing exemplary embodiment having a plurality of burr members has been described with respect to cells cultured between burr members, cells may additionally be cultured elsewhere in the microrobot structure. For example, cells may be cultured within an orifice of one of pores of the porous body of embodiments having a plurality of burr members. Moreover, it should be appreciated that the three-dimensional structure of microrobots of embodiments (e.g., mircrorobot 100 of the illustrated embodiment) herein facilitates three-dimensional cell cultures, such as is useful for sustaining the structural and functional complexities of the cells.
Microrobot 100 of the illustrated embodiment is a magnetically driven biocompatible microrobot configuration. Accordingly, microrobot 100 of embodiments comprises a magnetic layer and a biocompatible layer configured to carry and deliver cells to desired sites. The magnetic layer of embodiments may be provided on some portion or all of a surface of microrobot 100, such as to coat porous body 110 and/or burr members 120. The biocompatible layer of embodiments may likewise be provided on some portion or all of a surface of the microrobot, such as to coat porous body 110 and/or burr members 120, possibly coating some or all of the aforementioned magnetic layer.
The magnetic layer of microrobot 100 of embodiments is provided for configuring the microrobot to be controlled with an external magnetic field, such as to enable the magnetic microrobot to be positioned at a target site without the use of surgery or mechanical instrument. Accordingly, a type of magnetic layer material, sufficient amount of magnetic layer material, and/or a placement of magnetic layer material upon the microrobot structure may be selected according to embodiments to facilitate control of the microrobot. In accordance with embodiments of the invention, the magnetic layer material is provided so as to be thick enough to facilitate magnetism that is strong enough to control movement of the microrobot while being thin enough to accommodate a deposit time for the material that is conducive to efficient manufacturing processes. For example, the magnetic layer material of embodiments of microrobot 100 is preferably 50-300 nm thick, and more preferably 100-200 nm thick. Magnetic material of magnetic layer of microrobot 100 may comprise a metal having a suitable level of magnetism for facilitating control of the microrobot, and without significant corrosiveness (reactivity). The composition of the magnetic layer may, for example, include nickel (Ni), iron (Fe), cobalt (Co), and neodymium (Nd), or a combination thereof. A preferred embodiment of microrobot 100 comprises a magnetic layer formed from a metal composition containing Ni.
The biocompatible layer of microrobot 100 of embodiments is provided for configuring the microrobot for improved biostability and biocompatibility. Accordingly, a type of biocompatible layer material, a sufficient amount of biocompatible layer material, and/or a placement of biocompatible layer material upon the microrobot structure may be selected according to embodiments to facilitate cell cultivation and adhesion on the microrobot. In accordance with embodiments of the invention, the biocompatible layer material provided so as to be thick enough that suitable biocompatibility is facilitated while being thin enough to accommodate a deposit time for the material that is conducive to efficient manufacturing processes. For example, the biocompatible layer of embodiments of microrobot 100 is preferably 10-50 nm in thick. Biocompatible material of magnetic layer of microrobot 100 may comprise a metal exhibiting a high biocompatibility for facilitating microrobot biostability and biocompatibility. The composition of the biocompatible layer may, for example, include titanium (Ti), medical stainless steel, alumina (Al2O3), and gold (Au), or a combination thereof. A preferred embodiment of microrobot 100 comprises a biocompatible layer formed from a metal composition containing Ti.
In operation according to the illustrated embodiment of flow 200 shown in
It should be appreciated that, although the foregoing example of forming a porous microrobot structure described with respect to block 210 uses a lithographic technique, embodiments of the present invention may use additional or alternative techniques in forming porous microrobot structures of a magnetically driven biocompatible microrobot. For example, operation to form porous microrobot structure in accordance with block 210 of embodiments of the invention may use epitaxy, molecular deposition, microextrusion, particulate leaching, emulsion freeze-drying, fused deposition modeling (FDM), etc.
Having formed the underlying porous microrobot structure for the magnetically driven biocompatible microrobot, flow 200 of the illustrated embodiment proceeds to block 220 wherein a magnetic layer material is disposed upon a surface of the porous microrobot structure. For example, a deposition technique, such as electron beam deposition, dipping, electroplating, sputtering, chemical vapor deposition, direct metal deposition, etc., may be used to deliver a magnetic layer material to an outer surface of the porous microrobot structure (as represented by step 320 of
After forming the magnetic layer, flow 200 of the illustrated embodiment proceeds to block 230 wherein a biocompatible layer material is disposed upon a surface of the porous microrobot structure. For example, a deposition technique, such as electron beam deposition, dipping, electroplating, sputtering, chemical vapor deposition, direct metal deposition, etc., may be used to deliver a biocompatible layer material to an outer surface of the porous microrobot structure (as represented by step 330 of
Having the magnetic layer and biocompatible layer formed upon the porous microrobot structure, a magnetically driven biocompatible microrobot of embodiments is provided after completion of block 230 of flow 200. The resulting magnetically driven biocompatible microrobot may, for example, be utilized as a targeted cells carrying microrobot. Accordingly, the microrobot of embodiments may be introduced to a cell culture in order for a plurality of cells to be cultured in the structure of the microrobot (e.g., cells cultured between adjacent ones of the burr members of an embodiment having a plurality of burr members, cells cultured within an orifice of one of pores of an embodiment without burr members, etc.), as represented by step 340 of
Magnetically driven biocompatible microrobots configured as shown in
As shown in
The control experiment of
Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.
