WO2008056837A1 - Procede de fabrication de reseau de biomateriau par photoreaction - Google Patents

Procede de fabrication de reseau de biomateriau par photoreaction Download PDF

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Publication number
WO2008056837A1
WO2008056837A1 PCT/KR2006/004646 KR2006004646W WO2008056837A1 WO 2008056837 A1 WO2008056837 A1 WO 2008056837A1 KR 2006004646 W KR2006004646 W KR 2006004646W WO 2008056837 A1 WO2008056837 A1 WO 2008056837A1
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WO
WIPO (PCT)
Prior art keywords
biomaterial
substrate
pso
fabricating
array
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Application number
PCT/KR2006/004646
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English (en)
Inventor
Min-Gon Kim
Yong-Beom Shin
Bong Hyun Chung
Jun Hyoung Ahn
Hyou-Arm Joung
Original Assignee
Korea Research Institute Of Bioscience And Biotechnology
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Application filed by Korea Research Institute Of Bioscience And Biotechnology filed Critical Korea Research Institute Of Bioscience And Biotechnology
Priority to PCT/KR2006/004646 priority Critical patent/WO2008056837A1/fr
Publication of WO2008056837A1 publication Critical patent/WO2008056837A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00427—Means for dispensing and evacuation of reagents using masks
    • B01J2219/00432—Photolithographic masks
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00596—Solid-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00709—Type of synthesis
    • B01J2219/00711—Light-directed synthesis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00722—Nucleotides

Definitions

  • the present invention relates to a method for fabricating a biomaterial array using photoreaction, and more particularly to a method for fabricating a biomaterial array, comprising modifying a substrate surface with psoralen (PSO) to prepare a substrate having a PSO surface formed thereon, and immobilizing biomaterials (e.g., DNA, proteins, etc.) on the substrate having PSO surface using photoreaction.
  • PSO psoralen
  • Biomaterial array technology has been applied to DNA microarrays, protein chips, etc. and is emerging as an important technology in genomics, proteomics and clinical diagnostic studies.
  • a step of immobilizing biomaterials on surfaces is necessarily required.
  • DNA modification is required to immobilize DNA on a surface.
  • a method of immobilizing amine-, thiol- or biotin-terminated DNA on a surface is used.
  • pin-based dispensing or inkjet spray method is generally used, and thus it is difficult to control the spot size to 50 ⁇ m or less.
  • a technology of controlling the spot size to 10 ⁇ m or less is required, because it makes it easy to measure a very small amount of a sample.
  • the spotting method is used to fabricate arrays, the amount of spotting transferred to a surface is not constant, thus reducing the reproducibility of the arrays.
  • the present inventors have made extensive efforts to develop a method of fabricating a biomaterial array, in which a biomaterial is immobilized on a substrate without needing separate modification of the biomaterial. As a result, the present inventors have found that a biomaterial can be immobilized on a substrate modified with PSO by photoreaction, thereby completing the present invention.
  • PSO psoralen
  • Another object of the present invention is to provide a biomaterial array fabricated by said method.
  • the present invention provides a method for fabricating a biomaterial array, the method comprising the steps of: (a) modifying a substrate surface with psoralen (PSO), thereby preparing a substrate having a PSO surface formed thereon; and (b) bringing a biomaterial into contact with the substrate having the PSO surface, and then irradiating the substrate with light, thereby immobilizing the biomaterial on the substrate.
  • PSO psoralen
  • the step (a) preferably comprises (i) modifying the substrate with an amine group and then treating the substrate with PSO-NHS, or (ii) modifying the substrate with streptavidin and then attaching PSO-biotin to the substrate. Also, the inventive method further comprises, before the step (a), a step of coating the substrate surface with a hydrophilic material selected from the group consisting of dextran, PEG, cellulose and levan.
  • a mask is preferably placed in a path of irradiating the light, and the light is preferably focused light having a wavelength of 300-600 nm.
  • the substrate is preferably made of a material selected from the group consisting of glass, quartz, glass wafers, silicon wafers, fused silica, plastics and transparent polymers.
  • the biomaterial is at least one selected from the group consisting of proteins, peptides, amino acids, DNA, PNA, enzyme substrates, ligands, cofactors, carbohydrates, lipids, oligonucleotides and RNA.
  • the present invention provides a biomaterial array, which is fabricated according to said method and comprises a biomaterial bound to a PSO surface on a substrate.
  • FIG. 1 schematically shows a method for fabricating a biomaterial according to the present invention.
  • Reference numerals in FIG. 1 denote the following components:
  • PSO Psoralen
  • FIG. 2 shows fluorescent images selectively hybridized with SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3.
  • a SEQ ID NO: 1
  • b SEQ ID NO: 2
  • c SEQ ID NO 3.
  • FIG. 3 is a fluorescent scanning image of a fabricated antibody microarray with which Alexa Fluor® 488-labelled goat anti-mouse IgGl( ⁇ l) reacted.
  • FIG. 4 is a fluorescence image of a fabricated antibody microarray with which IL-5 selectively reacted.
  • FIG. 5 is a fluorescence image of an oligonucleotide array having a spot size of less than 10 ⁇ m, fabricated using a shadow mask.
  • the present invention relates to a method for fabricating a biomaterial array, comprising bringing a biomaterial into contact with a substrate having a psoralen (PSO) surface formed thereon, and then irradiating the substrate with light to immobilize the biomaterial on the substrate. Also, the present invention relates to a biomaterial array, which is fabricated by said method and comprises a biomaterial immobilized on a PSO surface on a substrate.
  • PSO psoralen
  • FIG. 1 schematically shows a method for fabricating a biomaterial array.
  • a material which is used to treat a substrate in order to bring a biomaterial into contact with the substrate surface, is a psoralen (PSO) having a structure of Formula 1.
  • PSO psoralen
  • PSO is generally used in DNA tagging and is known to photoreact with DNA molecules while intercalating with DNA. Also, PSO does not react with water, but efficiently reacts with biomaterials. However, there has not been any attempt to make an array using such a material.
  • the present invention provides a method capable of fabricating various biomaterial arrays by modifying a substrate surface with PSO on the basis of the characteristics of PSO.
  • PSO-NHS is allowed to react with an amine- modified surface
  • PSO-biotin can be bound to a streptavidin-immobilized surface.
  • a substrate having a PSO surface formed thereon can be used to fabricate a biomaterial array.
  • a DNA microarray is fabricated by treating a PSO-modified surface with DNA solution using a microarrayer, irradiating the surface with UV light to allow DNA to react with PSO, and then washing the surface.
  • a general method of fabricating a DNA microarray requires a process of modifying DNA ends with an amine group or thiol group, but the inventive method as described above has an advantage in that the process of modifying DNA is not required.
  • an antibody microarray can be fabricated by treating a PSO-modified surface with an antibody using a microarrayer, irradiating the surface with UV light for a given time to allow the antibody to react with PSO, and then washing the surface.
  • a general method of fabricating a protein microarray has a problem in that the fabricated protein array has reduced protein stability, whereas the present invention has an advantage in that protein activity is not decreased because the irradiation wavelength of UV light and the time of exposure to light are controlled to 300-600 nm and 30 minutes, respectively.
  • the method of fabricating the biomaterial array using photoreaction has an advantage in that the irradiation position of light can be easily controlled such that the biomaterial can be immobilized to a specific position.
  • Study results showing that a biomaterial was immobilized to a specific position in a micro flui die channel using photoreaction were presented (Holden et al. Anal. Chem., 76(7): 1838, 2004), and the photoreaction method of the present invention can be applied to microfluidic chips.
  • a biomaterial array having a very small spot size can be fabricated by bringing a specific biomaterial solution into contact with a PSO-modified surface, irradiating light at a desired specific position to be immobilized with the biomaterial, bringing another biomaterial solution into contact with the PSO-modified surface, and then irradiating light to a desired specific position to be immobilized with the biomaterial.
  • biomaterial array fabricated in a small area according to the above-described method is very useful for the measurement of a very small amount of a sample, such as the measurement of biomaterials in single cells.
  • a glass slide was immersed in a mixed solution of 95% sulfuric acid and 30% hydrogen peroxide (3:1 v/v) at 60-65 ° C for 20 minutes, and then washed sequentially with distilled water and ethanol.
  • the washed glass slide was immersed in an ethanol solution of 1% (3 ⁇ aminopropyl)trimethoxysilane (Aldrich, Milwaukee, WI, USA) at room temperature for about 30 minutes to form a self- assembled monomolecular film thereon, and then the glass slide surface was washed sequentially with ethanol and distilled water and dried with nitrogen gas.
  • a solution of 1% glutaraldehyde (Sigma, St. Louis, MO, USA) in PBS (phosphate- buffered saline, pH 7.4) was allowed to react with the dried glass slide surface for 1 hour to modify the surface with an aldehyde group.
  • a glass slide was immersed in a mixed solution of 95% sulfuric acid and 30% hydrogen peroxide (3: 1 v/v) at 60-65 ° C for 20 minutes, and then washed clean sequentially with distilled water and ethanol.
  • the washed glass slide was immersed in an ethanol solution of 1% (3-aminopropyl)trimethoxysilane at room temperature for about 30 minutes to form a self-assembled monomolecular film thereon, and then the glass slide surface was washed sequentially with ethanol and distilled water and dried with nitrogen gas.
  • a chip having the carboxyl-modified surface was immersed in a solution of 100 mM EDC (l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride) and 25 mM NHS (N-hydroxysuccinimide) in distilled water to activate the chip.
  • EDC l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Example 1-1 The glass slide having the PSO surface formed thereon, fabricated in Example 1-1, was placed on a microarrayer (Proteogen, CM-1000, Korea). Meanwhile, each of oligonucleotides (Proligo Primers & Probes) having SEQ ID NOS: 1-3, respectively, was dissolved in TE buffer (10 mM Tris-HCl. 1 mM EDTA, pH 8.0) containing 10% polyethyleneglycol (MW: 200, Sigma, St. Louis, MO, USA), at a concentration of 50 ⁇ g/m#, and each of the solutions was dispensed in a 384- microwell plate and then transferred into said microarrayer.
  • TE buffer 10 mM Tris-HCl. 1 mM EDTA, pH 8.0
  • polyethyleneglycol MW: 200, Sigma, St. Louis, MO, USA
  • SEQ ID NO: 1 5 1 -T15-ACTGCTGCCTCCCGTAG-3 l
  • SEQ ID NO: 2 5 l -T15-AAGGGTTGCGCTCGTTG-3 1
  • SEQ ID NO: 3 5'-T15-CTCTCTGTACCAGCCATTGT-3 t
  • the oligonucleotides of SEQ ID NOs: 1-3 were arrayed on the first, second and third lines of the glass slide, respectively, using a pin having a bore diameter of 335 ⁇ m.
  • the glass slide having the oligonucleotides arrayed thereon was irradiated with 365-nm UV light for 30 minutes and then washed with PBST (phosphate buffered saline: 0.01 M phosphate buffer with 0.138 M NaCl, 0.0027 M KCl, 0.05% Tween 20). Meanwhile, an oligonucleotide consisting of 15 T residues was dissolved in TE buffer containing 10% polyethyleneglycol (MW: 200), at a concentration of 50 ⁇ g/ml, and the solution was applied to cover the entire surface of the glass slide.
  • PBST phosphate buffered saline: 0.01 M phosphate buffer with 0.138 M NaCl, 0.0027 M KCl, 0.05% Tween 20.
  • PBST phosphate buffered saline: 0.01 M phosphate buffer with 0.138 M NaCl, 0.0027 M KCl, 0.05% Tween 20
  • the glass slide was exposed again to 365-nm UV light for 30 minutes, washed sequentially with PBST and DW, and dried with nitrogen gas, thus fabricating DNA microarrays.
  • SEQ ID NO: 4 Cy5-5'-CTACGGGAGGCAGCAGT-3'
  • SEQ ID NO: 5 Cy5-5'-CAACGAGCGCAACCCTT-3
  • SEQ ID NO: 6 Cy5-5'-ACAATGGCTGGTACAGAGAG-3'
  • Example 3 Fabrication and analysis of antibody microarrav 3-1 : Fabrication of antibody microarray
  • Example 1-1 The glass slide having the PSO surface formed thereon, fabricated in Example 1-1, was placed on a microarrayer (Proteogen, CM-1000, Korea). Meanwhile, each of BSA, an anti-interleukin-5 antibody and an anti-interferon-gamma antibody was dissolved in TE buffer containing 10% polyethyleneglycol (MW: 200), at a concentration of 0.2 mg/mL. Each of the protein solutions was dispensed in a 384-microwell plate, and then the microwell plate was transferred into said microarrayer.
  • TE buffer containing 10% polyethyleneglycol (MW: 200) 10% polyethyleneglycol
  • the control BSA solution, the anti-interleukin-5 antibody solution and the anti-interferon- gamma antibody solution were arrayed on the first, second and third lines of the glass slide, respectively, using a pin having a bore diameter of 335 ⁇ m.
  • the glass slide having the proteins arrayed thereon was irradiated with 365-nm UV light for 30 minutes and then washed with PBST.
  • BSA was dissolved in TEA buffer at a concentration of 1 mg/mL and applied to cover the entire surface of the glass slide.
  • the BSA-treated glass slide was exposed again to 365-nm UV light for 30 minutes, washed sequentially with PBST and DW, and then dried with nitrogen gas, thus fabricating a protein microarray.
  • the fabricated microarray was allowed to react with a solution of 10 ⁇ g/mL Alexa Fluor® 488-labelled goat anti-mouse IgGl( ⁇ l) (Molecular Probes, Eugene, Oregon, USA) in PBS for 30 minutes. Then, the microarray was washed sequentially with PBST and DW, dried with nitrogen gas and then analyzed with a fluorescent scanner (FIG. 3). As a result, as shown in FIG. 3, it could be seen that the antibodies were immobilized on the second and third lines.
  • Example 3-1 The antibody microarray fabricated in Example 3-1 was treated with a solution of 100 ng/mL IL-5 and 1 mg/mL BSA in PBS for 1 hour to induce antigen-antibody binding.
  • the chip was treated with an antibody for sensing the biotinylation of IL-5 and O.Olmg/m ⁇ Cy5-labeled Streptavidin in PBS containing 1 mg/mL BSA, such that the Cy5 fluorescent dye was bound to spots in which antigen-antibody binding occurred. Then, the chip was washed sequentially with PBST and DW, dried with nitrogen gas and then analyzed with a fluorescent scanner (see FIG. 4). As a result, as shown in FUG. 4, it could be seen that strong spots appeared on the second line, suggesting that the antigen-antibody reaction selective to IL-5 occurred.
  • the slide was mounted on a microscope (Carl Zeiss International), and experimental instruments were arranged such that light would be focused on the upper surface of the slide from a mercury lamp through a shadow mask (20 ⁇ m hole size, 20 ⁇ mcenter to center) at the iris, a 330-380 nm bandpass filter and a 10x optical lens. In this state, the slide was irradiated with UV light for 30 minutes and then washed with PBST, thus fabricating a DNA array.
  • a microscope Carl Zeiss International
  • the DNA array was allowed to react with a solution of 10 ⁇ g/mL streptavidin-Cy5 in PBS for 10 minutes, and then washed sequentially with PBST and DW, and the fluorescent image thereof was measured (see FIG. 5).
  • FIG. 5 it could be seen that an oligonucleotide pattern having small size was formed, and had a spot size of 9.7 ⁇ m as measured with a fluorescent microscope.
  • a biomaterial array can be fabricated using photoreaction without separate modification of a biomaterial, and thus the fabrication cost of the array can be reduced. Furthermore, when a biomaterial is immobilized using focused light, an array having a very small spot size, which is impossible with the prior microarray, can also be fabricated, thus making it possible to measure a very small amount of a sample.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Composite Materials (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Materials Engineering (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne un procédé de fabrication d'un réseau de biomatériau par photoréaction. Ce procédé consiste à modifier une surface de substrat au moyen de psoralène (PSO) pour obtenir un substrat sur lequel est formée une surface PSO; et à immobiliser des biomatériaux (de l'ADN, des protéines, etc.) sur le substrat à surface PSO par photoréaction. Selon l'invention, un biomatériau peut être immobilisé par photoréaction sans être modifié, ce qui permet de fabriquer un réseau de façon très simple et économique. Il est également possible, lorsqu'un biomatériau est immobilisé par une lumière dirigée, de fabriquer un réseau présentant une très petite taille de point, ce qui est impossible avec les microréseaux des antériorités.
PCT/KR2006/004646 2006-11-07 2006-11-07 Procede de fabrication de reseau de biomateriau par photoreaction WO2008056837A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2006/004646 WO2008056837A1 (fr) 2006-11-07 2006-11-07 Procede de fabrication de reseau de biomateriau par photoreaction

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Application Number Priority Date Filing Date Title
PCT/KR2006/004646 WO2008056837A1 (fr) 2006-11-07 2006-11-07 Procede de fabrication de reseau de biomateriau par photoreaction

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713326A (en) * 1983-07-05 1987-12-15 Molecular Diagnostics, Inc. Coupling of nucleic acids to solid support by photochemical methods
KR20000057427A (ko) * 1996-12-06 2000-09-15 마이클 제이. 헬러 광자 및 전자 용품을 위한 친화성 자가-어셈블리 시스템 및 디바이스
US6506895B2 (en) * 1997-08-15 2003-01-14 Surmodics, Inc. Photoactivatable nucleic acids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713326A (en) * 1983-07-05 1987-12-15 Molecular Diagnostics, Inc. Coupling of nucleic acids to solid support by photochemical methods
KR20000057427A (ko) * 1996-12-06 2000-09-15 마이클 제이. 헬러 광자 및 전자 용품을 위한 친화성 자가-어셈블리 시스템 및 디바이스
US6506895B2 (en) * 1997-08-15 2003-01-14 Surmodics, Inc. Photoactivatable nucleic acids

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