CN116058941A

CN116058941A - Device implantation method

Info

Publication number: CN116058941A
Application number: CN202310019730.5A
Authority: CN
Inventors: 段小洁; 蒋安琪; 刘杨; 孙洪吉; 贾荟琳; 杨子谦
Original assignee: Peking University
Current assignee: Peking University
Priority date: 2023-01-06
Filing date: 2023-01-06
Publication date: 2023-05-05

Abstract

An embodiment of the present disclosure provides a device implantation method, including: winding the device around at least one winding core; implanting the wound device into a target part of a target object; the wound device is unwound to unwind the device at the target site to complete implantation.

Description

Device implantation method

Technical Field

The present disclosure relates to the biomedical field, and in particular to a device implantation method.

Background

Cortical electroencephalogram ECoG is used clinically for detection of epileptic foci. Often, an open cranium procedure is required to implant a large electrode array into the cranium of a patient to detect epileptic signals. This type of surgery is risky for the patient who is required to bear the potential risk of surgical complications such as cerebral oedema, hematoma, cerebrospinal fluid leakage, etc. when receiving craniotomies. At the same time, removal of large pieces of skull may cause irreversible damage to the brain, and also lose landmark information (e.g., the bregma and bregma of rodents) located on the skull plate, affecting the accurate positioning of the electrodes.

Accordingly, it is desirable to provide a device implantation method that can implant large-area flexible electronics through tiny windows, reduce the damage caused by large-area bone removal, and reduce the risk of surgical infection.

Disclosure of Invention

According to one aspect of the present description, a device implantation method is provided. The method may include: winding the device around at least one winding core; implanting the wound device into a target part of a target object; the wound device is unwound to unwind the device at the target site to complete implantation.

Drawings

The present specification will be further elucidated by way of example embodiments, which will be described in detail by means of the accompanying drawings. The embodiments are not limiting, in which like numerals represent like structures, wherein:

FIG. 1 is a scene graph of an exemplary device implant according to some embodiments of the present description;

FIG. 2 is a flowchart of an exemplary process of a device implantation method according to some embodiments of the present description;

FIG. 3 is a flow chart of an exemplary process for preparing a device according to some embodiments of the present description;

FIG. 4 is a flowchart illustrating an exemplary process for winding a device according to some embodiments of the present description;

FIG. 5 is a schematic diagram of an exemplary process for winding a device according to some embodiments of the present description;

FIG. 6 is an exemplary schematic diagram of rat epileptic lower nerve signal recordings shown in accordance with some embodiments of the present disclosure;

fig. 7, 8 are exemplary schematic diagrams of device implants according to some embodiments of the present description;

FIG. 9 is a pictorial representation of the device implantation and unwinding on the rat subdural dura, according to some embodiments of the invention;

fig. 10 is a pictorial diagram illustrating an implementation of device post-implant unwinding under mini-pig dura according to some embodiments of the present disclosure.

Detailed Description

In order to more clearly illustrate the technical solutions of the embodiments of the present specification, the drawings that are required to be used in the description of the embodiments will be briefly described below. It is apparent that the drawings in the following description are only some examples or embodiments of the present specification, and it is possible for those of ordinary skill in the art to apply the present specification to other similar situations according to the drawings without inventive effort. Unless otherwise apparent from the context of the language or otherwise specified, like reference numerals in the figures refer to like structures or operations.

As used in this specification and the claims, the terms "a," "an," "the," and/or "the" are not specific to a singular, but may include a plurality, unless the context clearly dictates otherwise. In general, the terms "comprises" and "comprising" merely indicate that the steps and elements are explicitly identified, and they do not constitute an exclusive list, as other steps or elements may be included in a method or apparatus.

A flowchart is used in this specification to describe the operations performed by the system according to embodiments of the present specification. It should be appreciated that the preceding or following operations are not necessarily performed in order precisely. Rather, the steps may be processed in reverse order or simultaneously. Also, other operations may be added to or removed from these processes.

Fig. 1 is an application scenario diagram of an exemplary device implantation shown according to some embodiments of the present description. In some embodiments, as shown in fig. 1, an application scenario 100 may include a device 110, a target object 120.

The device 110 may include flexible electrodes for recording electrophysiological signals generated by neural activity in the subject 120, for stimulating cells to activate neurons, or for effecting sensing based on the content of bioactive or chemical substances contained in the body and changes thereof. In some embodiments, electrophysiological signals generated by neural activity within the target subject 120 can be recorded by implanting the device 110 at a target site of the target subject 120. In some embodiments, device 110 may be a flexible metal planar electrode array. In some embodiments, the device 110 may be a flexible mesh electrode.

In some embodiments, the electronic material layer of the device 110 is a conductive material that can still maintain high stability under mechanical deformation, such as a metal layer with nanometer thickness, a conductive polymer material, a carbon-based conductive material, and the like. In some embodiments, the device 110 may include an electrode array, a semiconductor transistor array, an integrated circuit, a biosensor, and the like. In some embodiments, the substrate material of the device 110 may be a flexible thin film material, such as Polyimide (PI), parylene-C, polydimethylsiloxane (PDMS), etc., with a thickness in the range of 1 μm to 30 μm.

In some embodiments, device 110 may be fabricated by a variety of fabrication methods including micro-nano processing techniques, thin film deposition techniques, and CMOS integrated circuit techniques, photolithography techniques, plasma etching techniques, and the like. For further description of the fabrication of the device, see fig. 3 and its associated description.

In some embodiments, the target object 120 may include, but is not limited to, a pig, mouse, human, or the like. In some embodiments, the target site of the target subject 120 comprises at least one of an intracranial, an intrathecal, an intrathoracic, and an intraperitoneal visceral organ, the intracranial comprising at least one of an epidural, and a subdural, the spinal cord comprising at least one of an epidural, and a subdural.

It should be noted that the application scenario 100 described above is provided for illustrative purposes only and is not intended to limit the scope of the present description. Various changes and modifications may be made by one of ordinary skill in the art in light of the description herein. However, such changes and modifications do not depart from the scope of the present specification.

Fig. 2 is a flow chart of an exemplary process of a device implantation method according to some embodiments of the present description. The operation of the process shown below is for illustrative purposes only. In some embodiments, process 200 may be accomplished with one or more additional operations not described and/or without one or more operations discussed. In addition, the order in which the operations of process 200 are illustrated in FIG. 2 and described below is not limiting.

Step 201, the device is wound around at least one winding core.

A winding core may refer to an article for winding a device. In some embodiments, the winding core may be a wire/tube (e.g., nickel titanium wire, nickel chromium wire, etc.), quartz tube, optical fiber, polymer wire/tube, etc. In some embodiments, the diameter of the winding core may range from 20 μm to 2mm. In some embodiments, the diameter of the winding core may range from 20 μm to 500 μm. In some embodiments, the diameter of the winding core may vary with the size of the device.

In some embodiments, the core may have a certain stiffness that may allow the device to be wound around the core. Simultaneously, the winding core can be deformed in the process of implanting the target part. For more details regarding the deformation of the winding core, reference is made to step 202 and the description thereof.

In some embodiments, at least one side of the device may be attached to at least one core using a water-soluble polymer or using perforation prior to winding the device around the at least one core. Wherein, the connection can mean that the two are attached together by bonding or the like.

The water-soluble polymer may be a material used to bond the device to the winding core.

In some embodiments, the water-soluble polymer may include at least polyethylene oxide (PEO), polyethylene glycol (PEG), silk proteins (silk),

Solution (+)>

MAE 100P)One of a biological glue, sucrose (sucrose) solution, gelatin (gelatine), etc.

The perforation means may be a means of passing the winding cores through a plurality of holes pre-punched in the device so that at least one side of the device is connected to at least one winding core. In some embodiments, the hole sites may be a variety of shapes, e.g., circular, diamond, etc. In some embodiments, the ratio of hole site diameter to core diameter may be 1.7:1-2:1.

In some embodiments, the at least one winding core may comprise one winding core. In some embodiments, a water-soluble polymer may be used or perforations may be used to attach one side of the device to the core. By way of example, when a core 420 is included, a water-soluble polymer may be used or perforations may be used to connect one side 410-1 of the device 410 to the core 420, as shown in fig. 4.

In some embodiments, the at least one winding core may comprise a first winding core and a second winding core. In some embodiments, the first side of the device may be attached to the first core and the second side of the device may be attached to the second core using a water-soluble polymer or using perforation. Wherein the first side and the second side may be located on opposite sides of the device. The first winding core and the second winding core differ in the location of attachment to the device. By way of example, as shown in FIG. 5, a first side 510-1 and a second side 510-2 are included in the device 510, the first side 510-1 and the second side 510-2 being located on opposite sides of the device 510. At least one of the winding cores comprises a first winding core 520-1, a second winding core 520-2, and the first side 510-1 of the device 510 can be connected to the first winding core 520-1 and the second side 510-2 of the device 510 can be connected to the second winding core 520-2 by using a water-soluble polymer or by using perforation.

In some embodiments, the means for connecting at least one side of the device to at least one winding core may further comprise placing the winding core in a groove after machining the groove in at least one side of the device and fixing, the groove being a polymeric groove prepared by micro-machining, the ratio of the groove size to the winding core size may be 2:1.

in some embodiments, after the at least one winding core is connected to the device, the at least one winding core may be wound from at least one side of the device. The manner in which the winding is performed may include, but is not limited to, manual winding by means of small electric devices, winding, etc.

In some embodiments, when at least one core comprises a core, the core may be wound from one side of the device until it merges with the other side of the device, resulting in a wound device. As an example, as shown in fig. 4, a winding core 420 may be wound from one side 410-1 of the device 410 to the other side 410-2 until it is brought together with the other side 410-2 of the device to obtain a wound device 430.

In some embodiments, when the at least one winding core includes a first winding core and a second winding core, the first winding core may be wound from a first side of the device in a first direction toward a center of the device, and the second winding core may be wound from a second side of the device in a second direction toward the center of the device until the first winding core and the second winding core are brought together to obtain a wound device.

The first direction may refer to a direction pointing from a first side of the device towards the center of the device. The second direction may refer to a direction pointing from a second side of the device towards the center of the device. The first direction and the second direction can be set manually.

As an example, as shown in fig. 5, a first winding core 520-1 may be wound from a first side 510-1 of a device 510 in a first direction 530-1 toward a center 510-3 of the device 510, and a second winding core 520-2 may be wound from a second side 510-2 of the device 510 in a second direction 530-2 toward the center 510-3 of the device 510 until the first winding core 520-1 and the second winding core 520-2 are brought together to provide a wound device 540.

In some embodiments, after the device is wound around at least one winding core, the wound device may be shaped with a water-soluble polymer. For example, the rolled device 430 or the rolled device 540 may be shaped with a water-soluble polymer.

In some embodiments, the manner in which the wound device is shaped may include a variety of ways. For example, the wound device may be shaped by applying a water-soluble polymer to both ends. For another example, the shaping may be performed by applying a water-soluble polymer to the side of the device after winding. This is not limiting in this specification.

Step 202, implanting the coiled device into a target site of a target object.

In some embodiments, the coiled device may be implanted into the target site of the target object through an opening at the target site of the target object. For example, two holes may be made in the human skull, the coiled device inserted through one side opening in the skull into the surface of the cerebral cortex, and the coiled wire exposed from the other side opening. For another example, a window of 6mm in length and 1mm in width may be opened in the cerebellum or lateral brain region of the mouse, and the coiled device may be implanted from the opening. For another example, a slit of 1.5cm length may be formed in front of and behind the dura mater of the mini pig, and the wound device may be implanted from the slit.

In some embodiments, at least one of the winding cores may deform during implantation at the target site to accommodate the shape of the target site. For example, when the target site has a certain curvature, at least one of the winding cores may be deformed from a straight shape to a curved shape having a certain curvature during implantation into the target site.

In some embodiments, at least one of the winding cores may maintain its current shape during implantation into the target site without deformation.

Step 203, unwind the wound device to unwind the device at the target site to complete implantation.

Unreeling may refer to the operation of unreeling the device after reeling.

In some embodiments, the rolled device may be unrolled into a planar state prior to rolling by unrolling. In some embodiments, the rolled device may also be unrolled into a curved state conforming to the target site by unrolling.

In some embodiments, the wound device may be rinsed with a first solution to dissolve the water-soluble polymer to unwind the wound device.

The first solution may be a solution for dissolving the water-soluble polymer. For example, the first solution may be physiological saline or the like.

In some embodiments, the wound device shaped with the water-soluble polymer is rinsed with a first solution, and the unwinding of the device is accomplished by pulling the winding core with forceps. Upon completion of the unwinding, the device may be deployed at the target site to complete the implantation. Schematic views of exemplary device implants are shown in fig. 7 and 8. Wherein fig. 7 is a schematic diagram of a small animal (e.g., rat, etc.) implant device, and fig. 8 is a schematic diagram of a large animal (e.g., mini pig, dog, macaque, etc.) implant device. An exemplary device unwind physical diagram is shown in fig. 9, 10. Wherein fig. 9 is a physical diagram for realizing implantation and unreeling of the device on the dura mater under the skull of the rat. Fig. 10 is a physical view of the device after implant unwinding under the dura mater of a mini pig. In some embodiments, after the unwinding is completed, the unwound device may be retained at the target site and after a sufficient flush with the first solution, the at least one core that has been separated from the device may be removed from the target object.

In some embodiments, after the device is "disconnected" from the at least one winding core at the target site, the at least one winding core may be removed from the target object and the unwound device will remain at the target site.

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.

Example 1 (Living body minimally invasive Implantation)

S1, injecting mannitol solution into a tail vein of a living body, reducing cranium pressure, reducing brain volume and providing intracranial space for implanting flexible electronic devices;

s2, opening two small windows on the skull, inserting the coiled device into the surface of the cerebral cortex through an opening on one side of the skull, and exposing the coiled core from an opening on the other side;

s3, flushing with physiological saline, dissolving the water-soluble polymer, and unwinding the flexible plane/mesh electronic device around the winding core until the flexible plane/mesh electronic device is completely unwound, so as to complete the living body minimally invasive implantation process of the large-area flexible/mesh electronic device.

Example 2 (minimally invasive implantation on the dura mater of rat skull)

S1, fixing a rat on a stereotactic instrument, removing body hair, scalp and other membranous layers, and exposing skull;

s2, mannitol is injected into tail vein to cause cerebral syneresis;

s3, drilling holes in cerebellum or contralateral brain areas, and embedding skull nails serving as ground electrodes;

s4, determining the shape and the position of the craniotomy, and drilling a hole by using a craniotomy drill. In the embodiment, the length of the skull opening is 6mm, and the width is 1mm;

s5, adjusting the nose fixed end of the front port of the stereotactic instrument, and lowering the nose and mouth so that the head of the rat is inclined, and implanting a coiled device from the skull opening at the moment;

s6, after the implantation process is finished, the front end of the stereotactic instrument is aligned, physiological saline wets the brain, the winding core is pulled out from the cranium by using forceps to assist the winding core to be completely unwound, and the winding core is pulled out from the cranium as shown in figure 9;

s7, placing back the skull small block, and fixing the craniotomy with biological silica gel, photosensitive resin or toothpaste cement and other materials.

In some embodiments of the present disclosure, implantation of large area electronics through a minimally invasive opening of the skull replaces removal of the entire skull (craniectomy) to place the large area electronics, which can significantly reduce damage to biological tissue, improve biocompatibility of biological tissue and electronics, avoid brain deformation, and reduce risk of damage to blood brain barrier.

Example 3 (Mini pig subdural minimally invasive implant)

S1, fixing a mini pig on a stereotactic instrument, and removing brain body hair, scalp and other membranous layers to expose skull;

s2, positioning by using an acupuncture needle, determining the shape and the position of an opening of the cranium, and drilling a hole by using a cranium drill. In the embodiment, the length of the skull opening is 5cm, the width is 2cm, and the dura mater is exposed;

s3, cutting an opening with the length of 1.5cm before and after the dura mater, and implanting a coiled device (the area of the device is 3cm x 1.5cm when the device is unfolded);

s4, operating tweezers to unwind the device around the winding core until the device is completely unwound under the dura mater, as shown in FIG. 10;

s5, extracting the separated winding cores from the lower part of the dura mater;

s6, placing the bone back to the skull, fixing the bone by using biological silica gel, and fixing the bone by using materials such as photosensitive resin or toothpaste cement.

In some embodiments of the present disclosure, implantation of a large-area electronic device into the subdural space through a minimally invasive opening of the dura mater, instead of removing the dura mater (dura mater removal), places the large-area electronic device, can significantly reduce damage to biological tissue, improve biocompatibility between the biological tissue and the electronic device, and avoid brain deformation and reduce risks such as damage to the blood brain barrier.

Example 4 (epileptic Signal acquisition)

A 128-site flexible planar nerve electrode can be implanted into the rat cortical epidural space through the opening in the rat skull by the implantation method described above. After the flexible planar nerve electrode is implanted into the epidural space of the rat cortex, electrophysiological signal acquisition can be performed: and (3) dripping an epileptic inducing drug 4-AP into the upper left corner of the flexible planar nerve electrode to induce the rat to generate epileptic signals. A well-characterized high quality epileptic nerve field potential signal as shown in fig. 6 can be recorded by the implanted flexible planar nerve electrode.

Fig. 3 is a flow chart of an exemplary process for preparing a device according to some embodiments of the present description. The operation of the process shown below is for illustrative purposes only. In some embodiments, process 300 may be accomplished with one or more additional operations not described and/or without one or more operations discussed. In addition, the order in which the operations of process 300 are illustrated in FIG. 3 and described below is not limiting. In some embodiments, process 300 may be used to prepare metallic Au flexible electrodes, the specific steps including:

in step 301, nickel is plated on the nickel sheet as a sacrificial layer.

Step 302, spin coating is performed on the upper layer of the sacrificial layer, and a layer of base material is covered as a base layer after high temperature.

And 303, carrying out positive photoresist photoetching on a substrate material, and carrying out electron beam coating or magnetron sputtering to obtain a metal Au/Cr electrode conductive layer pattern serving as a conductive layer of an electronic device.

And 304, uniformly coating the Au/Cr electrode patterns, and obtaining the insulating layer after high temperature.

And 305, performing positive photoresist photoetching again, and obtaining metal AI as a mask layer of the device through electron beam coating or magnetron sputtering.

And 306, etching the redundant insulating layer and the basal layer film to obtain the exposed electrode at the metal site.

Step 307, etching the sacrificial layer and the mask layer with ferric chloride, releasing the electrode from the silicon wafer, and cleaning with deionized water to obtain the prepared device.

It should be noted that the above description of process 300 is for purposes of example and illustration only and is not intended to limit the scope of applicability of the present disclosure. Various modifications and alterations to process 300 will be apparent to those skilled in the art in light of the present description. However, such modifications and variations are still within the scope of the present description.

The beneficial effects of the embodiment of the specification at least comprise: (1) The large-area electronic device is implanted through the minimally invasive opening of the skull, so that the large-area electronic device is placed instead of taking down the whole skull, damage to biological tissues can be obviously reduced, the biocompatibility of the biological tissues and the electronic device is improved, and risks such as cerebral deformation, damage to blood brain barriers and the like are avoided; (2) The preparation of the large-area planar flexible device is compatible with the current micro-nano processing technology, so that the processing of large-area high-density recording sites can be realized, the requirement of large-area multi-site recording neural activity in the current neural network research is met, and sufficient time-space division ratio is provided for the research of the dynamic neural network; (3) The specific type of the electronic device and the spatial distribution of the working sites can be customized according to the use requirement, winding can be performed by using one or two winding core wires according to the requirement, and winding cores can be made of different materials according to the requirement, so that the diversity of the deformable implanted electronic device is provided; (4) The device has no requirement on the structure and bending rigidity of the device, and can be matched with an ultra-flexible electronic device. The planar electronic device is soft, has mechanical strength close to that of nerve tissue, can be tightly attached to the surface of the biological tissue in a large range after being implanted and spread through a small-area opening, forms a seamless, conformal and efficient nerve interface, is beneficial to improving the quality and stability of nerve signal stimulation and recording, and can realize dynamic monitoring of large-area electrophysiological signal change of the cerebral cortex.

While the basic concepts have been described above, it will be apparent to those skilled in the art that the foregoing detailed disclosure is by way of example only and is not intended to be limiting. Although not explicitly described herein, various modifications, improvements, and adaptations to the present disclosure may occur to one skilled in the art. Such modifications, improvements, and modifications are intended to be suggested within this specification, and therefore, such modifications, improvements, and modifications are intended to be included within the spirit and scope of the exemplary embodiments of the present invention.

Meanwhile, the specification uses specific words to describe the embodiments of the specification. Reference to "one embodiment," "an embodiment," and/or "some embodiments" means that a particular feature, structure, or characteristic is associated with at least one embodiment of the present description. Thus, it should be emphasized and should be appreciated that two or more references to "an embodiment" or "one embodiment" or "an alternative embodiment" in various positions in this specification are not necessarily referring to the same embodiment. Furthermore, certain features, structures, or characteristics of one or more embodiments of the present description may be combined as suitable.

Furthermore, the order in which the elements and sequences are processed, the use of numerical letters, or other designations in the description are not intended to limit the order in which the processes and methods of the description are performed unless explicitly recited in the claims. While certain presently useful inventive embodiments have been discussed in the foregoing disclosure, by way of various examples, it is to be understood that such details are merely illustrative and that the appended claims are not limited to the disclosed embodiments, but, on the contrary, are intended to cover all modifications and equivalent arrangements included within the spirit and scope of the embodiments of the present disclosure. For example, while the system components described above may be implemented by hardware devices, they may also be implemented solely by software solutions, such as installing the described system on an existing server or mobile device.

Likewise, it should be noted that in order to simplify the presentation disclosed in this specification and thereby aid in understanding one or more inventive embodiments, various features are sometimes grouped together in a single embodiment, figure, or description thereof. This method of disclosure, however, is not intended to imply that more features than are presented in the claims are required for the present description. Indeed, less than all of the features of a single embodiment disclosed above.

Each patent, patent application publication, and other material, such as articles, books, specifications, publications, documents, etc., referred to in this specification is incorporated herein by reference in its entirety. Except for application history documents that are inconsistent or conflicting with the content of this specification, documents that are currently or later attached to this specification in which the broadest scope of the claims to this specification is limited are also. It is noted that, if the description, definition, and/or use of a term in an attached material in this specification does not conform to or conflict with what is described in this specification, the description, definition, and/or use of the term in this specification controls.

Finally, it should be understood that the embodiments described in this specification are merely illustrative of the principles of the embodiments of this specification. Other variations are possible within the scope of this description. Thus, by way of example, and not limitation, alternative configurations of embodiments of the present specification may be considered as consistent with the teachings of the present specification. Accordingly, the embodiments of the present specification are not limited to only the embodiments explicitly described and depicted in the present specification.

Claims

1. A device implantation method, the method comprising:

winding the device around at least one winding core;

implanting the coiled device into a target part of a target object;

and unreeling the reeled device to enable the device to be unreeled at the target site so as to finish implantation.

2. The method of claim 1, wherein the method further comprises:

at least one side of the device is connected to the at least one winding core before the device is wound around the at least one winding core.

3. The method of claim 2, wherein the at least one winding core comprises a first winding core and a second winding core, and wherein the connecting at least one side of the device to the at least one winding core comprises:

the first side of the device is connected to the first winding core with the water-soluble polymer or with perforation and the second side of the device is connected to the second winding core, the first side and the second side being on opposite sides of the device.

4. A method according to claim 3, wherein said winding said device around at least one winding core comprises:

winding the first winding core from the first side toward the center of the device in a first direction, and winding the second winding core from the second side toward the center of the device in a second direction until the first winding core and the second winding core are brought together.

5. The method of claim 1, wherein the method further comprises:

after the device is wound around at least one winding core, the wound device is shaped with a water-soluble polymer.

6. The method of claim 5, wherein unreeling the reeled device to unwind the device at the target site comprises:

and flushing the coiled device by adopting a first solution, and dissolving the water-soluble polymer to unwind the coiled device.

7. The method of claim 1, wherein the at least one winding core is deformed during implantation into the target site to conform to the shape of the target site.

8. The method of claim 2 or 5, wherein the water-soluble polymer comprises at least polyethylene oxide, polyethylene glycol, silk fibroin, and,

One of solution, biological glue, sucrose solution, gelatin.

9. The method of claim 1, wherein the device comprises a flexible mesh electrode.

10. The method of claim 1, wherein the target site comprises at least one of an intracranial, an intrathecal, an intrathoracic, and an intraperitoneal visceral, the intracranial comprising at least one of an epidural, a subdural, and the intrathecal comprising at least one of an epidural, a subdural.