Self-unfolding implanted electrode adopting degradable packaging and preparation method thereof

Abstract

The invention provides a self-expanding implanted electrode adopting degradable packaging and a preparation method thereof.The self-expanding implanted electrode comprises a plurality of electrodes and electrode connecting wires electrically connected with the electrodes, and the electrode connecting wires converge to form an electrode connecting wire harness. Shape memory layers are respectively adhered to the upper side and the lower side of each group of connected electrodes and electrode connecting wires, and each shape memory layer has a contraction state and an expansion state; the shape memory layer can be folded and shrunk with the electrode and the electrode connecting line to form a bunchy structure in a shrunk state, and the exterior of the bunchy structure is coated with a degradable packaging layer for a human body. The packaging layer can be naturally decomposed in a body after being used, the implanted electrode can be automatically unfolded from a contraction state under a driving condition, and the area after unfolding can be increased by more than hundreds of times, so that the number and the area of holes in the electrode implanting process are effectively reduced, the purpose of minimally invasive surgery is achieved, and meanwhile, the influence of subsequent removal surgery is reduced to the minimum.

Description

Technical Field

[0001] The present invention relates to brain-computer interface technology, and in particular to a self-expanding implant electrode using a degradable package and a preparation method thereof. Background Art

[0002] The brain is the human's higher nerve center, in which the intricate neural network composed of billions of neurons realizes human daily language, learning, thinking and decision-making. The transmission signals between synapses mainly include the transmission of chemical transmitters and electrical signals. Neuroscience is a key issue in brain neuroscience research. Brain-computer interface technology is the latest technology that converts neuronal activity into user commands. It does not rely on peripheral nerves and muscles, establishes an information communication and control channel between the brain and external devices, and establishes a bridge between the brain and the machine. In the medical field, brain-computer interfaces can be used to reconstruct the neural control ability and muscle signal transmission function of paralyzed patients in vitro, thereby improving their quality of life, or can be used to diagnose and treat neurological diseases such as Parkinson's disease and stroke.

[0003] Neural microelectrodes used in brain-computer interfaces are divided into fully invasive electrodes, semi-invasive electrodes, and surface electrodes. Unlike non-invasive brain-computer interfaces that place electrodes on the scalp, the electrodes of invasive brain-computer interfaces are inside the brain, so that high-quality signals can be collected. At present, the electrodes of invasive brain-computer interfaces generally use ECoG cortical electrodes. ECoG cortical electrodes are rectangular or strip-shaped, placed under the dura mater, and can cover a large range of cerebral cortex. High-density and large-area electronic interfaces are key components of brain-computer interface technology. However, this type of electrode requires craniotomy and opening of the dura mater to be implanted. The dura mater is a protective membrane for the brain, and opening it will cause the brain to lose protection. In addition, the skull window is generally larger than the actual cortical electrode area. Craniotomy brings many surgical risks, such as bleeding, late infection, and postoperative aesthetics. Brain-computer interface has become a new direction for the development of future science and technology. Although the existing implanted electrodes and microelectrodes can reduce surgical trauma, they cannot simultaneously guarantee high-density and large-area interface applications. Facing the future communication needs of high data volume, it is difficult to achieve good results. Summary of the invention

[0004] In view of the shortcomings in the prior art, the present invention provides a self-expanding implantable electrode with degradable packaging and a preparation method thereof. The packaging layer will also naturally decompose in the body after use. The electrode can automatically expand from a contracted state under driving conditions, and the area after expansion can be increased by more than a hundred times, thereby effectively reducing the number and area of ​​openings during the electrode implantation process, achieving the purpose of minimally invasive surgery, and minimizing the impact of subsequent removal surgery.

[0005] The present invention achieves the above technical objectives through the following technical means.

[0006] A self-expanding implantable electrode with a degradable package, comprising a plurality of electrodes and electrode connecting wires electrically connected thereto, wherein the electrode connecting wires are gathered into an electrode connecting wire bundle, characterized in that a shape memory layer is adhered to the upper and lower sides of each group of connected electrodes and electrode connecting wires, respectively, and the shape memory layer has two states, namely, a contracted state and an expanded state, and can be transformed between the contracted and expanded states; the contour of the shape memory layer in the expanded state is consistent with the topological structure of the electrodes and the electrode connecting wires, and the shape memory layer can be folded and contracted with the electrodes and the electrode connecting wires into a bundle structure with a diameter of ≤1 mm in the contracted state; the initial state of the implantable electrode is a bundle structure in a contracted state, and a human body-degradable packaging layer is coated on the outside of the bundle structure;

[0007] The shape memory layer is an insulating poly (L-lactide-caprolactone-polylactic acid-glycolic acid) copolymer (PLCL-PLGA), and its glass transition temperature Tg is 55-65°C; the encapsulation layer is a maltose-silk fibroin composite film, and its degradation rate is 30-90 days, which matches the tissue healing cycle.

[0008] Furthermore, at least one group of reinforcing ribs is arranged between adjacent electrode connecting lines. The reinforcing ribs are PLCL-PLGA strips with a width of 50 to 100 μm. The shape memory response temperature of the PLCL-PLGA strips is lower than the glass transition temperature Tg of the main shape memory layer and is set to 45 to 50°C.

[0009] Furthermore, the thickness of the shape memory layer is 40-60 μm, and the thickness changes gradually along the electrode connection line (8), with the thickness near the electrode end being 60 μm and the thickness at the distal end being 40 μm, so as to match the stress distribution during unfolding.

[0010] Furthermore, the electrode surface integrates a chip sensor layer, including a composite structure of a strain sensor and a pH sensor, wherein the sensor layer is electrically connected to an electrode connection line through a through silicon via (TSV); the electrode connection line is an n-type doped semiconductor circuit on a single crystal silicon substrate with a doping concentration of 1×10 18 cm -3 , the surface is coated with SiO with a thickness of 150 to 250 nm 2 Insulation layer.

[0011] Furthermore, the shape of the end of the encapsulation layer 1 is wedge-shaped, with an inclination angle θ=15-30° and a surface roughness Ra≤0.1 μm, so as to reduce tissue damage during implantation.

[0012] The method for preparing the degradable packaged self-expanding implantable electrode is characterized by comprising the following steps:

[0013] (1) Preparation of shape memory layer: poly(lactic acid-co-glycolic acid) (PLGA) and poly(L-lactide-caprolactone) (PLCL) were mixed in a mass ratio of 3:7, dissolved in a 20% chloroform solution, and ultrasonically dispersed to a solid content of 15 wt % to obtain a shape memory polymer precursor;

[0014] (2) Shape memory layer micro-molding:

[0015] First, a glass substrate treated with silanization was used to make its surface contact angle ≥110°, and then the precursor was drop-coated on the glass substrate. The glass substrate was preheated to 38±2°C, and the coating thickness was controlled to 50±10μm through a microfluidic channel;

[0016] The wavelength is 365nm and the energy is 200±20mJ / cm 2 UV photolithography of electrodes and connecting lines, and developing to form a bottom shape memory layer (2);

[0017] (3) Sensor and circuit integration:

[0018] Laser-induced generation of through holes with a diameter of 10±2 μm on the bottom shape memory layer (2), and the through holes are filled with conductive silver paste (Ag content 85 wt%);

[0019] Growing an n-type doped layer on a single crystal silicon substrate by molecular beam epitaxy (MBE), and forming an electrode connection line (8) circuit by photolithography;

[0020] Atomic layer deposition (ALD) is used to generate ALD on the circuit surface. 2 O 3 Passivation layer;

[0021] (4) Hot pressing packaging and self-folding:

[0022] Covering the top shape memory layer (2) on the circuit layer, and hot pressing at 110° C. and 0.5 MPa pressure for 10 minutes to achieve interlayer bonding;

[0023] After cooling to room temperature, the composite was peeled off the substrate and left to stand in an environment with a humidity of ≤5% for 24 h, where it spontaneously shrank into a bundle;

[0024] (5) Degradable encapsulation layer coating:

[0025] Dissolve maltose and silk fibroin in deionized water at a mass ratio of 7:3 to form a 25wt% solution;

[0026] An encapsulation layer with a thickness of 50 μm was formed on the surface of the bundle electrode by electrospinning and then dried and solidified in vacuum at 60°C.

[0027] Furthermore, the step (2) also includes a reinforcing rib synchronous molding step, in which a reinforcing rib mold is generated between adjacent electrode connecting lines by ultraviolet photolithography again, and after the PLCL-PLGA precursor is poured, it is annealed at 80° C. for 2 hours to form a cross-linked structure.

[0028] Further, chip sensor manufacturing:

[0029] a. Silicon nanolayer treatment: Phosphorus diffusion for 5 minutes and boron diffusion for 20 minutes are performed on the silicon layer on the top of the SOI wafer at 1050°C to form a pn junction;

[0030] b. Sensor patterning: Spin-coating photoresist, and then performing reactive ion etching after exposure to form a strain-sensitive beam structure;

[0031] c. Metal interconnection: sputtering titanium / gold layer, photolithography to form electrode leads;

[0032] d. Protective layer coating: Spin-coat a copolymer of butylene adipate and butylene terephthalate (PBAT) and anneal at 80°C as a biocompatible encapsulation.

[0033] Furthermore, the method further comprises step (6) sharpening the end of the encapsulation layer: using a femtosecond laser to perform bevel cutting on the end of the encapsulation layer, with an inclination angle of θ=25°, and the thickness of the silk fibroin-PEG composite lubricating layer coated on the surface after cutting is 500±50nm.

[0034] The self-expanding implantable electrode with degradable encapsulation described in the present invention has an external encapsulation layer made of a material that is solid at room temperature and degradable in the human body, such as maltose, silk fibroin, etc. When the implantable electrode is implanted in the brain, the encapsulation layer can automatically degrade, and both sides of the exposed electrode are shape memory layers. Under human body temperature conditions, it automatically expands due to its own shape memory effect, achieving a small wound and a large electrode coverage area, reducing complications of electrode implantation surgery. And because the encapsulation layer 1 is a degradable material, when the electrode is removed, it can spontaneously combust and decompose in the body, minimizing the risk of removing the implanted electrode.

[0035] Furthermore, in the present invention, the shape of the end of the packaging layer is set to be wedge-shaped, so as to facilitate the implantation of the implantable electrode. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is a schematic diagram of the expanded state of the implanted electrode of the present invention;

[0037] Figure 2 is a schematic structural diagram of the implanted electrode of the present invention in a contracted state;

[0038] Figure 3 is a schematic cross-sectional structure diagram of the implanted electrode of the present invention;

[0039] Figure 4 It is a schematic diagram of the structure of the electrode tip disk.

[0040] 1- packaging layer, 2- shape memory layer, 3- electrode, 4- reinforcement rib, 5- electrode connecting wire harness, 21- bottom shape memory layer, 22- top shape memory layer, 8- electrode connecting wire, 9- chip sensor layer. DETAILED DESCRIPTION

[0041] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments, but the protection scope of the present invention is not limited thereto.

[0042] like Figure 1 , Figure 2 , Figure 3 , Figure 4 As shown, the self-expanding implantable electrode with degradable encapsulation of the present invention comprises a plurality of electrodes 3 and electrode connecting wires 8 electrically connected thereto, wherein the electrode connecting wires 8 converge into an electrode connecting wire bundle 5, and a layer of shape memory layer 2 is adhered to the upper and lower sides of each group of connected electrodes 3 and electrode connecting wires 8, respectively, and the shape memory layer 2 has two states of contraction and expansion, and can be transformed between the contraction and expansion states; the contour of the shape memory layer 2 in the expanded state is consistent with the topological structure of the electrode 3 and the electrode connecting wire 8. In the contracted state, the shape memory layer 2 can be folded and contracted with the electrode 3 and the electrode connecting wire 8 into a bundle structure with a diameter of ≤1 mm, and the initial state of the implantable electrode is a bundle structure in a contracted state, and the human body degradable encapsulation layer 1 is coated on the outside of the bundle structure.

[0043] The shape memory layer 2 is an insulating poly (L-lactide-caprolactone-polylactic acid-glycolic acid) copolymer (PLCL-PLGA), and its glass transition temperature Tg is 55-65°C; the encapsulation layer 1 is a maltose-silk fibroin composite film, and its degradation rate is 30-90 days, which matches the tissue healing cycle.

[0044] The thickness of the shape memory layer 2 is 40-60 μm, and the thickness changes gradually along the electrode connection line 8, with the thickness near the electrode end being 60 μm and the thickness at the far end being 40 μm, so as to match the stress distribution during unfolding.

[0045] Furthermore, at least one group of reinforcing ribs 4 is arranged between adjacent electrode connecting lines 8. The reinforcing ribs 4 are PLCL-PLGA strips with a width of 50 to 100 μm. The shape memory response temperature of the PLCL-PLGA strips is lower than the glass transition temperature Tg of the main shape memory layer 2 and is set to 45 to 50°C.

[0046] The surface of the electrode 3 is integrated with a chip sensor layer 9, which includes a composite structure of a strain sensor and a pH sensor. The sensor layer 9 is electrically connected to an electrode connection line 8 through a through silicon via (TSV); the electrode connection line 8 is an n-type doped semiconductor circuit on a single crystal silicon substrate with a doping concentration of 1×10 18 cm -3 , the surface is coated with SiO with a thickness of 150-250nm 2 Insulation layer.

[0047] The shape of the end of the encapsulation layer 1 is wedge-shaped, with an inclination angle θ=15-30° and a surface roughness Ra≤0.1 μm, so as to reduce tissue damage during implantation.

[0048] The method for preparing the degradable packaged self-expanding implantable electrode is characterized by comprising the following steps:

[0049] (1) Preparation of shape memory layer precursor:

[0050] Poly(lactic acid)-co-glycolic acid (PLGA) (Mw=80 kDa, GA / LA=50 / 50) and poly(L-lactide)-caprolactone (PLCL) (Mw=120 kDa, CL / LLA=30 / 70) were mixed in a mass ratio of 3:7, dissolved in a 20% chloroform solution, and ultrasonically dispersed to a solid content of 15 wt% to obtain a shape memory polymer precursor.

[0051] (2) Shape memory layer micro-molding:

[0052] First, a glass substrate treated with silanization was used to make its surface contact angle ≥110°, and then the precursor was drop-coated on the glass substrate. The glass substrate was preheated to 38±2°C, and the coating thickness was controlled to 50±10μm through a microfluidic channel;

[0053] The wavelength is 365nm and the energy is 200±20mJ / cm 2 The electrode and connecting line patterns are formed by ultraviolet photolithography, and the shape memory layer 2 is formed after development.

[0054] (3) Sensor and circuit integration:

[0055] A through hole with a diameter of 10±2 μm is generated by laser induction on the bottom shape memory layer 21, and the through hole is filled with a conductive silver paste with an Ag content of 85 wt%;

[0056] The n-type doped layer was grown on a single crystal silicon substrate by molecular beam epitaxy (MBE), with a phosphorus doping concentration of 1×10 19 cm -3 , photolithography to form an electrode connection line 8 circuit;

[0057] Atomic layer deposition (ALD) is used to generate ALD on the circuit surface.2 O 3 Passivation layer, thickness 50nm.

[0058] (4) Hot pressing packaging and self-folding:

[0059] Cover the top shape memory layer 22 on the circuit layer and heat press at 110°C and 0.5MPa pressure for 10 minutes to achieve interlayer bonding;

[0060] After cooling to room temperature, the composite was peeled off from the substrate and allowed to stand in an environment with a humidity of ≤5% for 24 hours to shrink spontaneously into a bundle.

[0061] (5) Degradable encapsulation layer coating:

[0062] Maltose (DE value ≥ 95%) and silk fibroin (molecular weight 200kDa) were dissolved in deionized water at a mass ratio of 7:3 to form a 25wt% solution; an encapsulation layer 1 with a thickness of 50μm was formed on the surface of the bundle electrode by electrospinning at a voltage of 15kV and a receiving distance of 20cm, and then vacuum dried and solidified at 60°C.

[0063] Sharpening of the end of the encapsulation layer: A femtosecond laser with a wavelength of 1030 nm and a pulse energy of 50 μJ was used to perform bevel cutting on the end of the encapsulation layer 1, with an inclination angle of θ=25°. After cutting, the surface was coated with a silk fibroin-PEG composite lubricating layer with a thickness of 500 nm.

[0064] Furthermore, in the reinforcing rib synchronous forming step, a reinforcing rib 4 mold is generated between adjacent electrode connecting lines 8 by secondary photolithography, and after the PLCL-PLGA precursor is poured, it is annealed at 80° C. for 2 hours to form a cross-linked structure.

[0065] The two shape memory layers 2 are divided into a bottom substrate layer and a top encapsulation layer. The manufactured shape memory layer includes electrodes, the bearing part of the electrode connection wires and reinforcing ribs, and is a spider web-like structure. The shape memory layer used for the top encapsulation layer has the same shape as that used for the bottom substrate layer, but the middle part of the top encapsulation layer is a through-hole structure, which facilitates the passage of the electrode connection wire bundle 5 formed by the electrode connection wire parts.

[0066] The chip sensor manufacturing process is as follows:

[0067] a. Silicon nanolayer processing: Phosphorus diffusion for 5 min and boron diffusion for 20 min were performed on the top silicon layer of the SOI wafer with a top silicon layer of 400 nm and a buried oxide layer of 1 μm at 1050°C to form a pn junction;

[0068] b. Sensor patterning: Spin-coat photoresist AZ5214 with a thickness of 1.5 μm, and after exposure, reactive ion etching (CF4 / O2=4:1, power 100 W) to form a strain-sensitive beam structure;

[0069] c. Metal interconnection: sputtering titanium / gold layer, photolithography to form electrode leads; the Ti layer is 20nm, and the Au layer is 200nm;

[0070] d. Protective layer coating: Spin-coat 20 μm of a copolymer of butylene adipate and butylene terephthalate (PBAT) at an annealing temperature of 80° C. to provide a biocompatible package for protection.

[0071] The embodiments are preferred implementations of the present invention, but the present invention is not limited to the above-mentioned implementations. Any obvious improvements, substitutions or modifications that can be made by those skilled in the art without departing from the essential content of the present invention belong to the protection scope of the present invention.

Claims

1. A self-expanding implantable electrode with a degradable package, comprising a plurality of electrodes (3) and electrode connecting wires (8) electrically connected thereto, wherein the electrode connecting wires (8) are gathered into an electrode connecting wire bundle (5), characterized in that: A shape memory layer (2) is adhered to the upper and lower sides of each group of connected electrodes (3) and electrode connecting wires (8), respectively. The shape memory layer (2) has two states, namely, contraction and expansion, and can be switched between the contraction and expansion states. The contour of the shape memory layer (2) in the expansion state is consistent with the topological structure of the electrodes (3) and the electrode connecting wires (8). In the contracted state, the shape memory layer (2) can be folded and contracted with the electrodes (3) and the electrode connecting wires (8) to form a bundle structure with a diameter of ≤1 mm. The initial state of the implanted electrode is a bundle structure in a contracted state, and a human-degradable encapsulation layer (1) is coated on the outside of the bundle structure. The shape memory layer (2) is an insulating poly (L-lactide-caprolactone-polylactic acid-glycolic acid) copolymer (PLCL-PLGA), and its glass transition temperature Tg is 55-65°C; the encapsulation layer (1) is a maltose-silk fibroin composite film, and its degradation rate is 30-90 days, which matches the tissue healing cycle.

2. The self-expanding implantable electrode according to claim 1, characterized in that: At least one group of reinforcing ribs (4) is arranged between adjacent electrode connection lines (8); the reinforcing ribs (4) are PLCL-PLGA strips with a width of 50 to 100 μm; the shape memory response temperature of the PLCL-PLGA strips is lower than the glass transition temperature Tg of the main shape memory layer (2), and is set to 45 to 50°C.

3. The self-expanding implantable electrode according to claim 1, characterized in that: The thickness of the shape memory layer (2) is 40-60 μm, and the thickness changes gradually along the electrode connection line (8), with the thickness near the electrode end being 60 μm and the thickness at the distal end being 40 μm, so as to match the stress distribution during unfolding.

4. The self-expanding implantable electrode according to claim 1, characterized in that: The electrode (3) surface is integrated with a chip sensor layer (9), comprising a composite structure of a strain sensor and a pH sensor, wherein the sensor layer (9) is electrically connected to an electrode connection line (8) via a through silicon via (TSV); the electrode connection line (8) is an n-type doped semiconductor circuit on a single crystal silicon substrate, and the surface is coated with a SiO2 insulating layer with a thickness of 150 to 250 nm.

5. The self-expanding implantable electrode according to claim 1, characterized in that: The end of the encapsulation layer (1) is wedge-shaped, with an inclination angle of θ=15-30° and a surface roughness Ra≤0.1 μm, so as to reduce tissue damage during implantation.

6. A method for preparing the self-expanding implantable electrode according to any one of claims 1 to 5, characterized in that The following steps are involved: (1) Preparation of shape memory layer precursor: Poly(lactic acid-co-glycolic acid) (PLGA) and poly(L-lactide-caprolactone) (PLCL) were mixed in a mass ratio of 3:7, dissolved in a 20% chloroform solution, and ultrasonically dispersed to a solid content of 15 wt % to obtain a shape memory polymer precursor; (2) Shape memory layer micro-molding: First, a glass substrate treated with silanization was used to make its surface contact angle ≥110°, and then the precursor was drop-coated on the glass substrate. The glass substrate was preheated to 38±2°C, and the coating thickness was controlled to 50±10μm through a microfluidic channel; The wavelength is 365nm and the energy is 200±20mJ / cm 2 UV photolithography of electrodes and connecting lines, and developing to form a shape memory layer (2); (3) Sensor and circuit integration: Laser-induced generation of through holes with a diameter of 10±2 μm on the bottom shape memory layer (21), and the through holes are filled with conductive silver paste; Growing an n-type doped layer on a single crystal silicon substrate by molecular beam epitaxy (MBE), and forming an electrode connection line (8) circuit by photolithography; Using atomic layer deposition (ALD) to generate an Al2O3 passivation layer on the circuit surface; (4) Hot pressing packaging and self-folding: Covering the top shape memory layer (22) on the circuit layer, and hot pressing at 110° C. and 0.5 MPa pressure for 10 minutes to achieve interlayer bonding; After cooling to room temperature, the composite was peeled off the substrate and left to stand in an environment with a humidity of ≤5% for 24 hours to shrink spontaneously into a bundle; (5) Degradable encapsulation layer coating: Maltose and silk fibroin are dissolved in deionized water at a mass ratio of 7:3 to form a 25wt% solution; an encapsulation layer (1) with a thickness of 50 μm is formed on the surface of the bundle electrode by electrostatic spinning, and then vacuum dried at 60°C for solidification.

7. The preparation method according to claim 6, characterized in that: The method also includes a reinforcing rib synchronous molding step, wherein a reinforcing rib (4) mold is generated between adjacent electrode connecting lines (8) by secondary photolithography, and after the PLCL-PLGA precursor is poured, annealing is performed at 80° C. for 2 hours to form a cross-linked structure.

8. The preparation method according to claim 6, characterized in that: The chip sensor manufacturing process is as follows: a. Silicon nanolayer processing: Phosphorus and boron are diffused on the top silicon layer of the SOI wafer to form a pn junction; b. Sensor patterning: Spin-coating photoresist, and then performing reactive ion etching after exposure to form a strain-sensitive beam structure; c. Metal interconnection: sputtering titanium / gold layer, photolithography to form electrode leads; d. Protective layer coating: Spin coating of copolymer of butylene adipate and butylene terephthalate (PBAT) as a biocompatible encapsulation.

9. The preparation method according to claim 6, characterized in that: The method further comprises the step (6) sharpening the end of the packaging layer: using a femtosecond laser to perform bevel cutting on the end of the packaging layer (1), with the inclination angle θ being 15 to 30°.

10. The preparation method according to claim 9, characterized in that: After femtosecond laser cutting, the thickness of the silk fibroin-PEG composite lubricating layer was 500±50nm.

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