Method of implantation of a medical device into neural tissue

Abstract

A method of providing a channel in nervous tissue filled with an aqueous gel for implantation of a microelectrode or other medical device lacking sufficient physical stability for direct implantation by insertion, comprises providing an apparatus comprising an oblong rigid pin covered by a dry gel forming agent; locating a target in the tissue; defining a straight insertion path a desired tissue insertion point and the target; aligning the pin with its end foremost with the insertion path; inserting the pin into the tissue to a position near or at the target; allowing sufficient time to pass for a gel to be formed around the pin, withdrawing the pin. Also disclosed is a corresponding channel; a method of implantation of a microelectrode or microprobe into nervous tissue via the channel; a corresponding method of implantation of living cells; a corresponding apparatus for forming the channel.

1 . A method of providing an oblong linear channel in nervous tissue of a person or a mammal for implantation of a medical device or other object into said tissue by insertion into the channel, the device being insufficiently physically stable for implantation by direct insertion into the tissue, the method comprising: providing a channel-forming apparatus comprising a rotationally symmetric, in particular cylindrical, rigid pin of a length exceeding the length of the channel to be provided and having a front end and a rear end, a section of the pin extending from its front end towards its rear end of a length corresponding to at least the length of the channel enclosed by a layer of gel forming agent or comprising gel forming agent, wherein a gel forming agent is a dry agent capable of forming an aqueous gel on contact with aqueous body fluid, the layer of gel forming agent or comprising gel forming agent comprising less than 20% by weight of water, preferably less than 10% by weight, in particular less than 5% or 2% by weight; inserting the pin into nervous tissue with its front end foremost; allowing aqueous gel to be formed around the pin by contact of gel forming agent with aqueous body fluid; withdrawing the pin from the gel; wherein the pin is sufficiently rigid to allow it to be inserted into nervous tissue in absence of the layer comprising or consisting of gel forming agent. 
     
     
         2 . The method of  claim 1 , wherein the pin comprises two or more layers comprising or consisting of gel forming agent, wherein each of said two or more layers comprises a different gel forming agent. 
     
     
         3 . The method of  claim 1 , wherein the pin is electrically conducting and/or comprises an axially extending electrical conductor and/or comprises an optical fiber. 
     
     
         4 . The method of  claim 1 , wherein the pin is of a metal or comprises a metal conductor or an electrically conducting non-metallic material such as an electrically conducting polymer or electrically conducting carbon. 
     
     
         5 . The method of  claim 1 , wherein the pin comprises a centrally disposed axially extending channel and optionally one or more channels extending radially from the axial channel. 
     
     
         6 . The method of  claim 1 , wherein a gel forming agent comprises gel-forming protein or carbohydrate. 
     
     
         7 . The method of  claim 6 , wherein the protein is selected from the group consisting of gelatin, hyaluronic acid and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid and salts thereof. 
     
     
         8 . The method of  claim 7 , wherein the protein is gelatin. 
     
     
         9 . The method of  claim 3 , wherein a metallic lead is attached in an electrically conducting fashion to the pin or the metal conductor or the electrically conducting polymer at or near the rear end thereof. 
     
     
         10 . The method of  claim 9 , wherein the lead is for connection with a voltage monitoring device or with a source of electric power. 
     
     
         11 . The method of  claim 3 , wherein the pin is electrically insulated except for at its front end. 
     
     
         12 . The method of  claim 1 , wherein a gel forming agent or a layer comprising a gel forming agent comprises a pharmacologically active agent, in particular a pharmacologically active agent selected from the group consisting of coagulant, anticoagulant, antibiotic, osmotic pressure adjusting agent, anti-inflammatory agent, nutrient, factor stimulating growth, factor stimulating cell differentiation, hormone, cytokine. 
     
     
         13 . The method of  claim 1 , wherein the apparatus comprises a microelectrode and/or an optical fiber. 
     
     
         14 . The method of  claim 5 , wherein said centrally disposed axially extending channel is designed for injection of aqueous fluid in an axial direction into the implantation channel. 
     
     
         15 . The method of  claim 14 , wherein the axially extending channel is in fluid communication with one or more radially extending channels allowing injection of said fluid in a radial direction into the implantation channel. 
     
     
         16 . A method of implantation of a microelectrode into nervous tissue, comprising:
 i) providing a microelectrode with a front end and a rear end, the microelectrode not being sufficiently rigid for insertion into nervous tissue;   i) forming a linear implantation channel in the tissue by the method of  claim 1 ;   iii) inserting the microelectrode with its front end foremost into said channel to a desired depth.   
     
     
         17 . A method for implantation of living cells into neural tissue, comprising:
 i) providing an aqueous suspension of living cells in a syringe with a needle or a pipette;   ii) forming a linear implantation channel in the tissue filled with aqueous gel according to the method of  claim 1 ;   iii) inserting the syringe needle or pipette to a desired depth into the implantation channel;   iv) injecting the aqueous suspension of living cells into the implantation channel;   v) withdrawing the syringe needle or pipette;   with the proviso that injection can be made prior to and/or during withdrawal.   
     
     
         18 . A method for implantation of living cells into neural tissue, comprising:
 i) providing a frozen aqueous suspension of living cells attached to the tip of an insertion bar;   ii) forming a linear implantation channel in the tissue filled with aqueous gel according to  claim 1 ;   ii) inserting the bar with its tip foremost to a desired depth into the implantation channel;   iv) allowing the frozen suspension to thaw;   v) withdrawing the bar.   
     
     
         19 . Apparatus for forming a linear channel in nervous tissue for implantation of a medical device, comprising or consisting of an oblong rigid pin having a front end and a rear end and a layer comprising or consisting of dry gel forming agent disposed on a pin section extending from the front end in a distal direction and enclosing said section, wherein said layer or agent contains less than 20% by weight of water, preferably less than 10% by weight, most preferred less than 5% by weight, wherein the pin is sufficiently rigid to allow it to be inserted into nervous tissue in absence of its layer comprising or consisting of dry gel forming agent. 
     
     
         20 . The apparatus of  claim 19 , wherein the pin is cylindrical. 
     
     
         21 . The apparatus of  claim 19 , wherein the pin is of metal or comprises metal. 
     
     
         22 . The apparatus of  claim 21 , wherein the metal is selected from steel, titanium, tungsten, hafnium, and iridium. 
     
     
         23 . The apparatus of  claim 19 , wherein the pin is of a polymer material or comprises such material. 
     
     
         24 . The apparatus of  claim 23 , wherein the polymer is acrylate or epoxy polymer. 
     
     
         25 . The apparatus of  claim 23 , wherein the polymer is reinforced with fiber, in particular carbon fiber. 
     
     
         26 . The apparatus of  claim 19 , comprising one or more means selected from electrode means, optical fiber means, sensor means. 
     
     
         27 . The apparatus of  claim 20 , wherein the pin comprises an axially extending channel opening at the distal face thereof. 
     
     
         28 . The apparatus of  claim 27  comprising channel(s) extending radially from the axial channel. 
     
     
         29 . The apparatus of  claim 28 , wherein the axially extending channel and/or a radially extending channel is plugged at its opening at the distal face or the cylindrical face, respectively, of the pin. 
     
     
         30 . The apparatus of  claim 29 , wherein the plug is of a material dissolvable or degradable in an aqueous fluid. 
     
     
         31 . The apparatus of  claim 19 , wherein the agent capable of forming a gel in contact with aqueous body fluid comprises a gel-forming protein or carbohydrate. 
     
     
         32 . The apparatus of  claim 31 , wherein the protein is selected from a biocompatible gel forming agent, in particular an agent selected from the group consisting of gelatin, hyaluronic acid and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid and salts thereof. 
     
     
         33 . The apparatus of  claim 19 , wherein the layer comprises a pharmacologically active agent. 
     
     
         34 . The apparatus of  claim 33 , wherein the pharmacologically active agent is selected from the group consisting of coagulant, anticoagulant, antibiotic, osmotic pressure adjusting agent, anti-inflammatory agent, nutrient, factor stimulating growth, factor stimulating cell differentiation, hormone. 
     
     
         35 . The apparatus of  claim 19 , comprising a friction reducing layer disposed on the entire dry gel forming layer or a portion thereof. 
     
     
         36 . The apparatus of  claim 19 , comprising a dissolution retarding layer disposed on the dry gel forming layer or a portion thereof. 
     
     
         37 . The apparatus of  claim 36 , comprising a friction reducing layer disposed on the dissolution retarding layer. 
     
     
         38 . A method of reducing microglia response to implantation of a medical device or other object into neural tissue, comprising providing a layer of a biocompatible aqueous gel surrounding the implanted device or object. 
     
     
         39 . The method of  claim 38 , wherein the layer of biocompatible gel is provided in form of a channel extending from a surface of the nervous tissue. 
     
     
         40 . The method of  claim 39 , wherein the medical device or other object is inserted into the tissue via the channel. 
     
     
         41 . The method of  claim 38 , wherein the biocompatible gel is selected from the group consisting of gelatin gel, hyaluronic acid gel and gel of salts thereof, chemically modified gelatin gel, chemically modified hyaluronic acid gel and gel of salts thereof. 
     
     
         42 . The method of  claim 41 , wherein the biocompatible gel is gelatin gel or chemically modified gelatin gel. 
     
     
         43 . The method of  claim 1 , wherein a gel forming agent is selected from the group consisting of: arabinogalactan; arabinoxylan; galactan; galactomannan; lichenan; xylan; cellulose derivatives such as hydroxymethylpropyl cellulose; whey protein; soy protein; casein; hyaluronic acid; chitosan; gum Arabic; carboxyvinyl polymer; sodium polyacrylate; carboxymethyl cellulose; sodium carboxymethyl cellulose; pullulan; polyvinylpyrrolidone; karaya gum; pectin; xanthane gum; tragacanth; alginic acid; polyoxymethylene; polyimide; polyether; chitin; poly-glycolic acid; poly-lactic acid; co-polymer of poly-glycolic and poly-lactic acid; co-polymer of poly-lactic acid and polyethylene oxide; polyamide; polyanhydride; polycaprolactone; maleic anhydride copolymer; poly-hydroxybutyrate co-polymer; poly(1,3-bis(p-carbophenoxy)propane anhydride); polymer formed by co-polymerization with sebacic acid or with poly-terephthalic acid; poly(glycolide-co-trimethylene carbonate); polyethylene glycol; polydioxanone; polypropylene fumarate; poly(ethyl glutamate-co-glutamic acid); poly(tert-butyloxy carbonylmethyl glutamate); poly-caprolactone; poly(caprolactone-co-butylacrylate); poly-hydroxybutyrate and copolymers thereof; poly(phosphazene); poly(D,L-lactide-co-caprolactone); poly(glycolide-co-caprolactone); poly(phosphate ester); poly(amino acid); poly(hydroxybutyrate); polydepsidpeptide; maleic anhydride copolymer; polyphosphazene; polyiminocarbonate; poly[(7.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethlyene carbonate)]; polyethylene oxide; hydroxypropylmethylcellulose, poly(ethylene-co-vinyl acetate); isobutylene-based copolymer of isobutylene and at least one other repeating unit such as butyl acrylate: butyl methacrylate; substituted styrene such as amino styrene, hydroxy styrene, carboxy styrene, sulfonated styrene; homopolymer of polyvinyl alcohol; co-polymer of polyvinyl alcohol and at least one other repeating unit such as a vinyl cyclohexyl ether; hydroxymethyl methacrylate; hydroxyl- or amino-terminated polyethylene glycol; acrylate-based copolymer such as methacrylic acid, methacrylamide, hydroxymethyl methacrylate; ethylene vinyl alcohol copolymer; silicone based copolymer of aryl or alkyl siloxane and at least one repeating unit; polyurethane; heparan sulfate; RGD peptide; polyethylene oxide; chrondroitin sulfate; YIGSR peptides; keratan sulfate; VEGF biomimetic peptide; perlecan (heparan sulfate proteoglycan 2); Ile-Lys-Val-Ala-Val (IKVAV) containing laminin alpha-1 chain peptide; modified heparin; fibrin fragments. 
     
     
         44 . Linear channel in nervous tissue of a person or animal for implantation of a medical device, the channel filled with aqueous gel formed in situ by contact of body fluid with dry biocompatible gel forming agent provided on a solid support, in particular a member of the group consisting of gelatin, hyaluronic acid and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid and salts thereof, wherein the support has been removed after forming the channel. 
     
     
         45 . The linear nervous tissue channel of  claim 44  filled with gel formed by contact of aqueous body fluid with one or more gel forming agents of the group consisting of: arabinogalactan; arabinoxylan; galactan; galactomannan; lichenan; xylan; cellulose derivatives such as hydroxymethylpropyl cellulose; whey protein; soy protein; casein; hyaluronic acid; chitosan; gum Arabic; carboxyvinyl polymer; sodium polyacrylate; carboxymethyl cellulose; sodium carboxymethyl cellulose; pullulan; polyvinylpyrrolidone; karaya gum; pectin; xanthane gum; tragacanth; alginic acid; polyoxymethylene; polyimide; polyether; chitin; poly-glycolic acid; poly-lactic acid; co-polymer of poly-glycolic and poly-lactic acid; co-polymer of poly-lactic acid and polyethylene oxide; polyamide; polyanhydride; polycaprolactone; maleic anhydride copolymer; poly-hydroxybutyrate co-polymer; poly(1,3-bis(p-carbophenoxy)propane anhydride); polymer formed by co-polymerization with sebacic acid or with poly-terephthalic acid; poly(glycolide-co-trimethylene carbonate); polyethylene glycol; polydioxanone; polypropylene fumarate; poly(ethyl glutamate-co-glutamic acid); poly(tert-butyloxy carbonylmethyl glutamate); poly-caprolactone; poly(caprolactone-co-butylacrylate); poly-hydroxybutyrate and copolymers thereof; poly(phosphazene); poly(D,L-lactide-co-caprolactone); poly(glycolide-co-caprolactone); poly(phosphate ester); poly(amino acid); poly(hydroxybutyrate); polydepsidpeptide; maleic anhydride copolymer; polyphosphazene; polyiminocarbonate; poly[(7.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethlyene carbonate)]; polyethylene oxide; hydroxypropylmethylcellulose, poly(ethylene-co-vinyl acetate); isobutylene-based copolymer of isobutylene and at least one other repeating unit such as butyl acrylate: butyl methacrylate; substituted styrene such as amino styrene, hydroxy styrene, carboxy styrene, sulfonated styrene; homopolymer of polyvinyl alcohol; co-polymer of polyvinyl alcohol and at least one other repeating unit such as a vinyl cyclohexyl ether; hydroxymethyl methacrylate; hydroxyl- or amino-terminated polyethylene glycol; acrylate-based copolymer such as methacrylic acid, methacrylamide, hydroxymethyl methacrylate; ethylene vinyl alcohol copolymer; silicone based copolymer of aryl or alkyl siloxane and at least one repeating unit; polyurethane; heparan sulfate; RGD peptide; polyethylene oxide; chrondroitin sulfate; YIGSR peptides; keratan sulfate; VEGF biomimetic peptide; perlecan (heparan sulfate proteoglycan 2); Ile-Lys-Val-Ala-Val (IKVAV) containing laminin alpha-1 chain peptide; modified heparin; fibrin fragments. 
     
     
         46 . The linear nervous tissue channel of  claim 44  of cylindrical form. 
     
     
         47 . The linear nervous tissue channel of  claim 46 , comprising two or more cylindrical layers of aqueous gel of same diameter as the channel. 
     
     
         48 . The linear nervous tissue channel of  claim 46 , wherein a cylindrical central layer of aqueous gel is surrounded by a peripheral layer of aqueous gel. 
     
     
         49 . The apparatus of  claim 19 , wherein a gel forming agent is selected from the group consisting of: arabinogalactan; arabinoxylan; galactan; galactomannan; lichenan; xylan; cellulose derivatives such as hydroxymethylpropyl cellulose; whey protein; soy protein; casein; hyaluronic acid; chitosan; gum Arabic; carboxyvinyl polymer; sodium polyacrylate; carboxymethyl cellulose; sodium carboxymethyl cellulose; pullulan; polyvinylpyrrolidone; karaya gum; pectin; xanthane gum; tragacanth; alginic acid; polyoxymethylene; polyimide; polyether; chitin; poly-glycolic acid; poly-lactic acid; co-polymer of poly-glycolic and poly-lactic acid; co-polymer of poly-lactic acid and polyethylene oxide; polyamide; polyanhydride; polycaprolactone; maleic anhydride copolymer; poly-hydroxybutyrate co-polymer; poly(1,3-bis(p-carbophenoxy)propane anhydride); polymer formed by co-polymerization with sebacic acid or with poly-terephthalic acid; poly(glycolide-co-trimethylene carbonate); polyethylene glycol; polydioxanone; polypropylene fumarate; poly(ethyl glutamate-co-glutamic acid); poly(tert-butyloxy carbonylmethyl glutamate); poly-caprolactone; poly(caprolactone-co-butylacrylate); poly-hydroxybutyrate and copolymers thereof; poly(phosphazene); poly(D,L-lactide-co-caprolactone); poly(glycolide-co-caprolactone); poly(phosphate ester); poly(amino acid); poly(hydroxybutyrate); polydepsidpeptide; maleic anhydride copolymer; polyphosphazene; polyiminocarbonate; poly[(7.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethlyene carbonate)]; polyethylene oxide; hydroxypropylmethylcellulose, poly(ethylene-co-vinyl acetate); isobutylene-based copolymer of isobutylene and at least one other repeating unit such as butyl acrylate: butyl methacrylate; substituted styrene such as amino styrene, hydroxy styrene, carboxy styrene, sulfonated styrene; homopolymer of polyvinyl alcohol; co-polymer of polyvinyl alcohol and at least one other repeating unit such as a vinyl cyclohexyl ether; hydroxymethyl methacrylate; hydroxyl- or amino-terminated polyethylene glycol; acrylate-based copolymer such as methacrylic acid, methacrylamide, hydroxymethyl methacrylate; ethylene vinyl alcohol copolymer; silicone based copolymer of aryl or alkyl siloxane and at least one repeating unit; polyurethane; heparan sulfate; RGD peptide; polyethylene oxide; chrondroitin sulfate; YIGSR peptides; keratan sulfate; VEGF biomimetic peptide; perlecan (heparan sulfate proteoglycan 2); Ile-Lys-Val-Ala-Val (IKVAV) containing laminin alpha-1 chain peptide; modified heparin; fibrin fragments.