WO2023121632A2 - Système de diagnostic de point d'intervention pour le diagnostic et le suivi de la phénylcétonurie - Google Patents

Système de diagnostic de point d'intervention pour le diagnostic et le suivi de la phénylcétonurie Download PDF

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Publication number
WO2023121632A2
WO2023121632A2 PCT/TR2022/051572 TR2022051572W WO2023121632A2 WO 2023121632 A2 WO2023121632 A2 WO 2023121632A2 TR 2022051572 W TR2022051572 W TR 2022051572W WO 2023121632 A2 WO2023121632 A2 WO 2023121632A2
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WIPO (PCT)
Prior art keywords
point
care system
chamber
cartridge
blood
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PCT/TR2022/051572
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English (en)
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WO2023121632A3 (fr
Inventor
Memed DUMAN
Caglar ELBUKEN
Deniz BAS
Ipek AKYILMAZ
Original Assignee
Bilkent Universitesi Ulusal Nanoteknoloji Arastirma Merkezi
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Priority claimed from TR2021/020698 external-priority patent/TR2021020698A2/tr
Application filed by Bilkent Universitesi Ulusal Nanoteknoloji Arastirma Merkezi filed Critical Bilkent Universitesi Ulusal Nanoteknoloji Arastirma Merkezi
Publication of WO2023121632A2 publication Critical patent/WO2023121632A2/fr
Publication of WO2023121632A3 publication Critical patent/WO2023121632A3/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6806—Determination of free amino acids
    • G01N33/6812—Assays for specific amino acids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502753—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0645—Electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0803—Disc shape
    • B01L2300/0806—Standardised forms, e.g. compact disc [CD] format
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502723—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders

Definitions

  • the present invention relates to a portable point-of-care diagnostic system which can determine the amount of phenylalanine in the blood by performing rapid blood analysis for early diagnosis and follow-up of phenylketonuria disease.
  • Phenylketonuria is a metabolic disease exhibiting autosomal recessive inheritance and it results from dysfunction of phenylalanine hydroxylase (PAH) enzyme which converts phenylalanine (PHE) amino acid into tyrosine amino acid.
  • PHE amino acid and its secondary metabolite products phenylpyruvate, phenyl lactic acid, etc.
  • Our Country ranks first in the world in terms of the prevalence of the said disease and its patient population. It is of vital importance to diagnose and start treatment and follow-up early due to the fact that mental deficiency can be avoided by means of phenylalanine-restricted diet therapy in patients diagnosed in the neonatal period.
  • Bacterial growth inhibition test (Guthrie), fluorometric immunoassay, enzymatic colorimetric test, HPLC (for direct amino acid analysis), and Tandem mass spectrometry (MS/MS) methods are used for phenylalanine measurement in the blood today. Since the first two methods may give false negative/positive results due to interference with antibiotics, they are not preferred in routine scans.
  • HPLC and MS/MS methods are fully automated and have high sensitivity and also require complex, quite high-cost equipment/devices and internal controls. Hospitals with advanced technical infrastructure are required for performing all these methods and well-trained healthcare personnel are needed for the interpretation of results correctly as well. Applications of these methods consist of a plurality of steps.
  • the patient’s blood is collected and then separated into blood plasma by means of centrifugation machines. Thereafter, the separated plasma is prepared as a sample for HPLC and MS/MS methods. Subsequently, measurements are started. This kind of devices require a waiting period of approximately 1 hour to stabilize the pressure, temperature, etc. before starting operation. Steps such as preparing specimen, measuring and then calculating the results as a numerical value extend the period for the result to be delivered to the patient considerably. The results are available to the patient approximately 24 hours after the sample is provided.
  • Blood PHE monitorization of patients is currently carried out by collecting venous blood and using HPLC method in healthcare centers where they are followed up.
  • the most significant disadvantages of this process include that biochemical monitoring of patients -particularly after the first year of age- cannot be performed as desired and their treatment cannot be provided in accordance with international standards due to the fact that the said process takes a long time, healthcare centers having the necessary technical equipment and personnel for metabolic diseases are scarce in our country, and most patients reside in cities far from metabolic centers. It is required to follow up the blood phenylalanine levels (once a week) closely and make dietary arrangements dynamically in patients who frequently enter the catabolic period, particularly in the first 2 years of age when childhood diseases such as infections predominate.
  • the International patent document no. W00218627 discloses a method of measurement for the simple and rapid determination of phenylalanine included in a biological specimen and a portable, compact test device.
  • An objective of the present invention is to realize a portable point-of-care diagnostic system which can determine the amount of phenylalanine in the blood by performing rapid blood analysis for early diagnosis and follow-up of phenylketonuria disease.
  • Another objective of the present invention is to realize a point-of-care diagnostic system which can be easily used by healthcare personnel following a short training for phenylalanine measurement from blood, is inexpensive and applicable in even community health centers in the smallest residential area.
  • Another objective of the present invention is to realize a point-of-care diagnostic system which does not require sample storage and transportation for phenylalanine measurement from the blood, and provides highly-accurate results in a short time.
  • Another objective of the present invention is to realize a point-of-care diagnostic system which includes all the steps such as sampling, centrifuging, testing, and providing numerical values; yields fast results, and is light and portable.
  • Another objective of the present invention is to realize a point-of-care diagnostic system which is based on a Lab-on-a-CD analysis system that enables to diagnose phenylketonuria disease early and follow-up its treatment process.
  • Figure l is a schematic view of the inventive system.
  • Figure 2 is an illustration of a cartridge included in the inventive system.
  • Figure 3 is an illustration depicting the layers of the cartridge included in the inventive system.
  • Figure 4 is a graph depicting the current values obtained as a result of an electrochemical reaction carried out with the blood plasma having different phenylalanine concentrations.
  • Figure 5 is a bar plot comparing the results obtained with the inventive system and the HPLC device for blood samples comprising different amounts of phenylalanine.
  • Figure 6 is a line plot comparing the results obtained with the inventive system and the HPLC device for blood samples comprising different amounts of phenylalanine.
  • the inventive point-of-care diagnostic system (1) which determines the amount of phenylalanine in the blood by performing rapid blood analysis for early diagnosis and follow-up of phenylketonuria disease comprises: at least one cartridge (2) wherein a blood specimen, which is a biological sample, is separated into its plasma and dripped so as to perform electrochemical measurement; at least one centrifugation device (3) which is configured to apply centrifugation transaction to the cartridge (2) in order to make the blood specimen, that is dripped onto the cartridge (2), is made ready for electrochemical measurement by separating it into its plasma; and at least one electronic device (4) which is in connection with the cartridge (2) and configured to measure the data of electrochemical changes occurring due to the amount of phenylalanine included in the blood specimen and to provide the same as a numerical value.
  • the cartridge (2) included in the inventive system (1) comprises preferably at least one filling chamber (21), preferably at least one separation chamber (22), preferably at least one pneumatic chamber (23), preferably at least one measuring chamber (24), and preferably at least one electrode connection receptacle (25).
  • the filling chamber (21) is a chamber wherein a blood specimen, the amount of phenylalanine included in thereof is aimed to be determined, is dropped and it has a ventilation hole.
  • the separation chamber (22) is a chamber wherein a blood specimen dropped into the filling chamber (21) is sent via a microchannel so as to be separated into its plasma by means of the centrifugal force generated by the initiation of rotation transaction.
  • the separation chamber (22) is a chamber wherein the blood is separated into its plasma since the pressure generated by the centrifugal force, that is generated by the effect of rotation, is less than the pressure generated in the chamber due to the blood sample and the compressed air.
  • the pneumatic chamber (23) is a chamber wherein the plasma is filled by passing through a microchannel by means of a piston effect occurring due to the fact that the pressure generated by the centrifugal force after reducing the rotational speed is greater than the pressure generated by the blood sample and the compressed air in the separation chamber (22), a or valve system.
  • the measuring chamber (24) is a chamber through which the plasma advances from the pneumatic chamber (23) by means of a microchannel with a siphon effect at reduced rotational speed, and it has a ventilation hole.
  • the measuring chamber (24) is a chamber wherein a nicotinamide adenine dinucleotide (NAD+) reagent and a phenylalanine dehydrogenase (PDH) enzyme that will perform an electrochemical reaction with the blood plasma by using electrochemical methods in the form of amperometry or voltammetry are added.
  • the measuring chamber (24) is a chamber being made of a conductive material in the form of silver, silver chloride, carbon, gold, platinum and comprising carbon nanotube-modified, carbon nanotube-graphene-modified, carbon nanotube-gold nanoparticle-modified, graphene-gold nanoparticle-modified, carbon nanofiber- modified, potassium ferrocyanide-modmed and quantum dot-modified electrodes (X).
  • the measuring chamber (24) is a chamber wherein the electrochemical reaction and the current changes resulting from the reaction are measured in order to determine the amount of phenylalanine in the blood plasma.
  • the measuring chamber (24) is an electronic module enabling to take measurement in a wide current range and realize high resolution, and being capable of performing electrochemical measurement.
  • the cartridge (2) comprises an upper layer (A), a first double-sided tape layer (B), a barrier (C), a second double-sided tape layer (D), a middle layer (E), a third double-sided tape layer (F) and a bottom layer (G), respectively from top to bottom.
  • the upper layer (A) has one each hole on the filling chamber (21) for blood sample/specimen inlet and ventilation, and an opening on the measuring chamber (24) for the inlet of reagents required for the electrochemical reaction and ventilation, and an opening in the size of the electrode connection receptacle (25).
  • the upper layer (A) is made of a blood-compatible material, preferably by polymethylmethacrylate (PMMA).
  • the first layer of doublesided tape (B) has an opening in the size of the filling chamber (21), the measuring chamber (24), the ventilation located on the filling chamber (21), and the electrode connection receptacle (25).
  • the barrier (C) has an opening in the size of the filling chamber (21), the measuring chamber (24), the ventilation located on the filling chamber (21), and the electrode connection receptacle (25).
  • the second doublesided tape layer (D) has an opening in the size of the chambers (21, 22, 23, 24), the channels extending between the chambers, and the electrode connection receptacle (25).
  • the middle layer (E) has an opening in the size of the chambers (21, 22, 23, 24), the channels extending between the chambers, and the electrode connection receptacle (25).
  • the middle layer (E) is made of a blood-compatible material and it is preferably produced by polymethylmethacrylate (PMMA).
  • the third doublesided tape layer (F) has an opening in the size of the chambers (21, 22, 23, 24), the channels extending between the chambers.
  • the bottom layer (G) has no openings and it is a layer containing the electrodes (X) and the electrode connection receptacle (25) that are used during the electrochemical reaction.
  • the bottom layer (G) is made of blood-compatible material and it is preferably produced by polymethylmethacrylate (PMMA).
  • the bottom layer (G) contains carbon nanotube-modified, carbon nanotube-graphene-modified, carbon nanotube-gold nanoparticle-modified, graphene-gold nanoparticle- modified, carbon nanofiber-modified, potassium ferrocyanide-modified and quantum dot-modified electrodes (X).
  • the cartridge (2) is obtained by superimposing all layers (A, B, C, D, E, F, G) so that the chambers are aligned with each other and assembling them by using any of the techniques such as laser bonding, solvent bonding, thermal bonding and ultrasonic wave fusion bonding, double-sided adhesive tape, lamination, mechanical bonding with screws by using seals.
  • the cartridge (2) can be produced by a molding process such that it comprises a bottom layer that contains at least one cavity for at least one chamber and an upper layer whereby samples are given and that contains the ventilation portions.
  • the cartridge (2) is disposable (single-use). In a preferred embodiment of the invention, the cartridge (2) is a microfluidic compact disc (CD). In another preferred embodiment of the invention, the cartridge (2) is a compact disc with standard electrodes.
  • the cartridge (2) enables to perform multiple measurements by designing a plurality of chambers, channels, and connection receptacles located thereon side by side.
  • the centrifugation device (3) included in the inventive the system (1) has an opening substantially of the same size as the cartridge (2) for the insertion of the cartridge (2) thereon and is suitable for receiving the cartridge (2).
  • the centrifugation device (3) is configured to apply rotational motion to the cartridge (2) inserted thereon.
  • the centrifugation device (3) is configured to provide adjustment of the rotation time and speed related to the rotational motion.
  • the centrifugation device (3) comprises at least one motor and a power supply for rotating the cartridge (2).
  • the electronic device (4) included in the inventive system (1) is configured to receive the values related to the current change that occur in the electrochemical reaction realized in the measuring chamber (24) by connecting to the electrode connection receptacle (25) in the cartridge (2) by means of the connection adapter.
  • the electronic device (1) is a device such as smartphone, tablet computer, desktop computer, or portable computer.
  • the electronic device (4) is configured to record the received values received related to the current change and to present them to the user upon being converted into a numerical value.
  • the electronic device (4) is configured to be connected to the electrode connection receptacle (25) when the reaction starts to take place after the centrifugation transaction of the cartridge (2) inserted on the centrifugation device (3) is completed and reagents are added into the measuring chamber (24) or reagents are attached to the surface of the electrodes included in the measuring chamber (24) depending on the measurement method.
  • the inventive system (1) is used as a Lab-on-a-CD system that enables to diagnose and follow-up phenylketonuria disease early. Furthermore, the system (1) is light, cost-effective, portable, capable of providing rapid numerical results and it can be easily used by healthcare professionals in all health centers following a brief explanation.
  • the cartridge (2) when it is started to rotate the cartridge (2) at 100-1500 G (gravitational force), 20-200 pL of blood sample is filled from the filling chamber (21) into the separation chamber (22).
  • the pressure of the air compressed in the separation chamber (22) is lower than the pressure of the centrifugal force and it starts to be compressed by the blood sample filling into the separation chamber (22).
  • the separation of blood into its plasma is completed in about 20 seconds.
  • the centrifugation speed is reduced to 300 rpm.
  • the cartridge (2) is rotated at this speed for a further 40 seconds.
  • the pressure of the compressed air and the blood sample in the separation chamber (22) becomes greater than the pressure of the centrifugal force and starts to expand.
  • air -intending to return to normal atmospheric pressure- performs a siphon and pushes the plasma into the pneumatic chamber (23).
  • the plasma received in the pneumatic chamber (23) fills the measuring chamber (24) by the siphoning effect.
  • the phenylalanine (Phe) dehydrogenase (PDH) enzyme spreads towards the electrode surface and reacts biocatalytically (T) in the presence of NAD+ to form phenylpyruvate and NADH:
  • Nicotinamide adenine dinucleotide (NAD+) and NADH in its reduced form is a coenzyme that fulfills a key role in enzymatic reactions catalyzed by dehydrogenases.
  • the structure of this coenzyme is based on two nucleotides derived from adenine and nicotinamide.
  • the nicotinamide-containing nucleotide is responsible for the electron transfer mediator function in biological systems.
  • the importance of the pair NAD+/NADH is based on the fact that this system is included in more than 300 enzyme reactions catalyzed by dehydrogenases. Therefore, the quantification of these compounds has significant importance both for the examination of redox biological processes and for the detection of various enzyme substrates.
  • the amperometric method is used in electrochemical measurements to be applied for PHE determination, and a potential of 0,65 V is applied for 2000 s.
  • the connection adapter is attached to the cartridge (2) and the measurement is initiated.
  • the mixture solution of enzyme (PDH) and NAD+ is added to the system from the hole included in the measuring chamber (24) and the reaction is initiated.
  • the current increases are observed in the measurement graphs according to the PHE amounts and the measurement is stopped after reaching the highest current value (approximately 10 min.).
  • a prototype is prepared for the inventive system (1) and a user interface is created on the electronic device (4).
  • the interface is user-friendly and quite self-easy-to- use.
  • each step is displayed after the previous transaction is completed.
  • the centrifugation is initiated by pressing the “start centrifuge” button.
  • the warning button “connect the connection adapter” is displayed.
  • the user presses this button and the "start electrochemical measurement” window is displayed.
  • the measurement is initiated and after about 10 minutes the "add reagent” window is displayed. After 10 minutes following this transaction, the amount of PHE in the blood is shown numerically in the on-screen box.
  • the interface also comprises a segment that displays graphs to follow the transactions during centrifugation and measurement.
  • the user has the opportunity to intervene in the event of an unexpected situation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Clinical Laboratory Science (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Microbiology (AREA)
  • Dispersion Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne un système de diagnostic de point d'intervention portable (1) qui peut déterminer la quantité de phénylalanine dans le sang en effectuant une analyse de sang rapide pour un diagnostic précoce et un suivi de la phénylcétonurie.
PCT/TR2022/051572 2021-12-22 2022-12-22 Système de diagnostic de point d'intervention pour le diagnostic et le suivi de la phénylcétonurie WO2023121632A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2021/020698 TR2021020698A2 (tr) 2021-12-22 Feni̇lketonüri̇ hastaliğinin teşhi̇si̇ ve taki̇bi̇nde kullanilan bi̇r hasta başi tani si̇stemi̇
TR2021020698 2021-12-22

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WO2023121632A2 true WO2023121632A2 (fr) 2023-06-29
WO2023121632A3 WO2023121632A3 (fr) 2023-09-14

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Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69832909T2 (de) * 1998-07-16 2006-09-14 Sapporo Immuno Diagnostic Laboratory, Sapporo Verfahren zum bestimmen von l-phenylalanin und ein l-phenylalaninsensor
TR2021019849A2 (tr) * 2021-12-14 2021-12-21 Gazi Ueniversitesi Rektoerluegue Kandan feni̇lalani̇n kanti̇tati̇f ölçümü yapan bi̇yosensör si̇stem

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