WO2008012705A2 - A photodiode for detection within molecular diagnostics - Google Patents
A photodiode for detection within molecular diagnostics Download PDFInfo
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- WO2008012705A2 WO2008012705A2 PCT/IB2007/052630 IB2007052630W WO2008012705A2 WO 2008012705 A2 WO2008012705 A2 WO 2008012705A2 IB 2007052630 W IB2007052630 W IB 2007052630W WO 2008012705 A2 WO2008012705 A2 WO 2008012705A2
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- H01L31/10—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof in which radiation controls flow of current through the device, e.g. photoresistors characterised by potential barriers, e.g. phototransistors
- H01L31/101—Devices sensitive to infrared, visible or ultraviolet radiation
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- H01L31/105—Devices sensitive to infrared, visible or ultraviolet radiation characterised by only one potential barrier the potential barrier being of the PIN type
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- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
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- H01L31/08—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof in which radiation controls flow of current through the device, e.g. photoresistors
- H01L31/10—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof in which radiation controls flow of current through the device, e.g. photoresistors characterised by potential barriers, e.g. phototransistors
- H01L31/101—Devices sensitive to infrared, visible or ultraviolet radiation
- H01L31/102—Devices sensitive to infrared, visible or ultraviolet radiation characterised by only one potential barrier
- H01L31/103—Devices sensitive to infrared, visible or ultraviolet radiation characterised by only one potential barrier the potential barrier being of the PN homojunction type
Definitions
- a photodiode for detection within molecular diagnostics A photodiode for detection within molecular diagnostics
- the invention relates to a photodiode, and in particular to a photodiode for detection within molecular diagnostics.
- Bio samples can be analyzed by illuminating the biological sample with a beam of light and detecting the scattered light.
- the fluorescence method is useful.
- the fluorescence method utilizes labeling agents that are capable of binding to particular sites of a molecule of the biological sample. When the sample is illuminated with a beam of light the labeling agent will emit light at a wavelength different from the wavelength of the illumination beam.
- the presence or absence of the specific target molecule can be determined. For instance, if the target molecules are labeled with a labeling agent, and if the target molecules subsequently bind to a probe molecule, the presence of the target molecule can be verified if fluorescent light is detected.
- target-probe molecule pairs are antibody-antigen, cell-antibody combinations and receptor-ligands pairs. Further examples include bonding or hybridization of for instance DNA-DNA pairs, RNA-RNA pairs and DNA-RNA hybrids.
- the detection system In order to detect the emitted light from the labeling agent, the detection system must be capable of detecting radiation having a particular wavelength of emitted radiation originating from the labeled agents. This is a problem since the biological sample typical will emit light both having the wavelength of the illumination light and the emitted light from the labeling agents. Accordingly, a method capable of discriminating between the wavelengths of the illumination light and the emitted light from the labeling agents would be advantageous.
- US 6,867,420 discloses a miniaturized optical excitation and detector system for detecting fluorescently labeled analytes in electrophoretic microchips and microarrays.
- the system uses miniature integrated components, light collection, optical fluorescence filtering, and an amorphous a-Si:H detector for detection.
- the collection of light is accomplished with proximity gathering and/or a micro-lens system.
- Optical filtering is accomplished by integrated optical filters.
- US 6,867,420 discloses a detection system where the emitted light it filtered by an integrated optical filter and detected with a photo detector. However, the detection system in US 6,867,420 is not simple.
- an improved detection system would be advantageous, and in particular a more efficient and/or reliable detection system would be advantageous.
- the invention preferably seeks to mitigate, alleviate or eliminate one or more of the above mentioned disadvantages singly or in any combination.
- a photodiode comprising, - a first semiconductor layer doped with a first impurity, said first semiconductor layer being adapted to receive incident radiation, said incident radiation having a spectral distribution with a center wavelength of at least 350 nm, a second semiconductor layer doped with a second impurity, a third semiconductor region, said third semiconductor region being capable of generating free electrons and free holes when excited with at least part of the incident radiation, wherein the incident radiation comprises radiation having a first spectral distribution and a second spectral distribution, where the first spectral distribution is spectrally shifted from the second spectral distribution, - the first semiconductor layer is capable of absorbing incident radiation having the first spectral distribution, wherein the absorption of radiation having the first spectral distribution does not significantly contribute with a photocurrent, the first semiconductor layer is capable of transmitting the incident radiation having the second spectral distribution, and the free electrons and free holes in the third semiconductor region generated by radiation having
- the invention is particularly, but not exclusively, advantageous for obtaining a simple detection system capable of discriminating between wavelengths by providing a photodiode having a first semiconductor layer capable of both absorbing incident radiation having a first spectral distribution without significantly generating a photocurrent and transmitting the incident radiation having a second spectral distribution.
- the photodiode may perform the desirable discrimination or filtering of wavelengths since the photodiode may be capable of discriminating between first and second spectral distributions by use of a simple photodiode.
- the photodiode may be capable of optically filtering away radiation having a first spectral distribution while simultaneously detecting radiation having a second spectral distribution.
- the first semiconductor layer is capable of absorbing incident radiation having a first spectral distribution, wherein the absorption of radiation having the first spectral distribution does not significantly contribute with a photocurrent. Accordingly, the ratio of photocurrent of the first spectral distribution and photocurrent of the second spectral distribution is insignificant, since the ratio is smaller than 1/80, preferably smaller than 1/90 or more preferred smaller than 1/99 in accordance with the absorption percentages of the first semiconductor layer.
- the photodiode may provide a simple detection system or device which, in addition, may be easily produced and, thereby, an inexpensive detection system may also be achieved by the photodiode.
- a photodiode or a photo detector that is simple enough and has sufficient filtering capabilities to filter away radiation having a first spectral distribution, so that the photodiode or photo detector can be built into or integrated with a detection apparatus, such as a micro total analysis system, a lab-on-a-chip or a molecular diagnostic system (MDx). That desirable object may be solved by the photodiode according to a first aspect of the invention.
- photodiode or a photo detector that is simple enough and sufficiently inexpensive to be utilized in a hand-held detection apparatus, such as molecular diagnostic system (MDx). That desirable object may be solved by the photodiode according to a first aspect of the invention.
- the photodiode may be integrated with a detection apparatus, since this may eliminate the risk of contaminating sensitive detection electronics. It may be desirable to have a cost effective photodiode having filtering capabilities without utilizing expensive external optical filters. That objective may be achievable by the photodiode according to a first aspect of the invention.
- the first semiconductor layer of the photodiode may have a thickness that is adapted to absorb the radiation having the first spectral distribution within a volume of the first semiconductor layer. Since it would be desirable to have a simple photodiode having filtering capabilities, this object may be achieved by adapting the thickness of the first semiconductor layer to absorb the radiation having the first spectral distribution, so as to obtain a filtering capability solely due to the thickness of the first semiconductor layer.
- Such thickness of the first semiconductor layer may be greater than 100 nm, preferably greater than 200 nm or more preferred greater than 300 nm in order to make the photodiode capable of discriminating between first and second spectral distributions.
- the thickness of the first semiconductor layer may be chosen so that the first semiconductor layer may be capable of absorbing at least 80 %, preferably at least 90 % or more preferred at least 99 % of the incident radiation having the first spectral distribution. It may be an advantage having a photodiode with a first semiconductor layer that is capable of absorbing for instance at least 99 % of the incident radiation, since an absorption of at least 99 % corresponds to filtering away at least 99 % of the first spectral distribution.
- the third semiconductor region may be a third layer of intrinsic semiconductor material positioned between the first semiconductor layer and the second semiconductor layer. Such a photodiode is referred to as a PIN diode or NIP diode.
- the photodiode is a PIN or NIP photodiode, since such photodiodes may have improved performance due a capability of generating higher photocurrent, having lower dark leakage, and higher sensitivity to incident radiation having the second spectral distribution.
- the photodiode according to a first aspect of the invention may have a first semiconductor layer which is a p doped layer, doped with acceptor impurities and, accordingly, a second semiconductor which is an n doped layer, doped with donor impurities.
- the photodiode may have a first semiconductor layer which an n doped layer doped with donor impurities and, accordingly, a second semiconductor layer which is a p doped layer doped with acceptor impurities.
- the choice of the order of the p doped layer and the n doped layers in relation to the respective first and second semiconductor layer is applicable both to the first type of photodiodes wherein the third semiconductor region is comprised by a part of the first semiconductor layer and a part of the second semiconductor layer, and to the second type of photodiodes where the third semiconductor region is a third layer of intrinsic semiconductor material positioned between the first semiconductor layer and the second semiconductor layer.
- the spectral shift between the first spectral distribution and the second spectral distribution may be at least 50 nm, preferably at least 100 nm, or more preferred at least 200 nm.
- the spectral shift or Stokes shift is at least 200 nm, since a large spectral shift improves the discrimination, or filtering effect, of wavelengths made by the photodiode.
- the first semiconductor layer and/or the second semiconductor layer may be made of such semiconductor materials as amorphous silicon (a-Si), amorphous silicon carbide (a-SiC), microcrystalline Si and low temperature polySi. It may be an advantage that different semiconductor materials can be used for semiconductor layers, as different semiconductor materials may have different absorbing capabilities. Accordingly, by choosing a particular semiconductor material the capability of the photodiode to filter away radiation having a first spectral distribution while detecting radiation having a second spectral distribution may be optimized.
- the photodiode may have an antireflection coating applied on the top face of the first semiconductor layer. It may be an advantage to have an antireflection coating on the top face of the first semiconductor layer, since the antireflection coating may increase the amount of incident radiation being transmitted into the first semiconductor layer.
- the present invention relates to a detecting apparatus capable of detecting the presence or absence, and optionally quantity, of a target molecule of a sample of a biological substance
- said detecting apparatus comprises, a processing device adapted to be provided with the sample containing target molecules, said processing device further being adapted to be provided with probe molecules for bonding with the target molecules, wherein the target molecules and/or probe molecules are labeled with labeling agents having luminescent properties, wherein said labeling agents emits radiation having a second spectral distribution when illuminated with radiation having a spectral distribution corresponding to the first spectral distribution, an illuminator capable of illuminating the sample with radiation having a spectral distribution corresponding to the first spectral distribution, and a photodiode according to a first aspect of the invention being capable of receiving emitted radiation comprising the first spectral distribution and the second spectral distribution, said emitted radiation being emitted from the sample, wherein the first spectral distribution is spectrally
- a detection apparatus capable of detecting the presence or absence, and optionally quantity, of a target molecule by detection of for instance fluorescent radiation from labeled target.
- a detection apparatus comprising a photodiode according to a first aspect of the invention, since the photodiode may be capable of discriminating between radiation having a first spectral distribution and radiation having a second spectral distribution.
- the sample of the biological substance may include such substances as cells, tissue sections, DNA, proteins, blood and urine. However, the sample may include other biological substances as well. Accordingly, the target molecule may be a molecule of the sample of the biological substance.
- the direction of the radiation from the illuminator may perpendicular to the normal of the surface of the first semiconductor layer, which may be an advantage since this reduces the amount of radiation having the first spectral distribution which is incident to the photodiode.
- the detection apparatus may comprise a second processing device capable of amplifying a concentration of DNA by Polymerase Chain Reaction. It may be an advantage to integrate other processing capabilities to the detection apparatus, such as Polymerase Chain Reaction, as this may increase the usability of the detection apparatus.
- the present invention relates to a method for detecting a target in a sample of a biological substance, said method comprises providing a detection apparatus with probe molecules for bonding with target molecules, wherein the target molecules and/or probe molecules are labeled with labeling agents having luminescent properties, wherein said labeling agents emits radiation having a second spectral distribution when illuminated with radiation having a spectral distribution corresponding to the first spectral distribution, providing the sample containing target molecules to the detection apparatus, illuminating the sample with radiation having a spectral distribution corresponding to the first spectral distribution, receiving emitted radiation from the sample by using a photodiode according to a first aspect of the invention, said emitted radiation comprising the first spectral distribution and the second spectral distribution, wherein the first spectral distribution is spectrally shifted from the second spectral distribution, the photodiode absorbs radiation having the first spectral distribution without significantly contributing with a photocurrent, said radiation being absorbed in the first semiconductor layer
- the first, second and third aspect of the present invention may each be combined with any of the other aspects.
- Fig. 1 is an illustration of a fluorescent detection system
- Fig. 2 is an illustration of a PIN photodiode according to the present invention
- Fig. 3 shows graphs showing the relation between the p layer semiconductor thickness and the wavelength of the incident radiation according to the present invention
- Fig. 4a shows the optical transmission of incident radiation power being transmitted through a first semiconductor layer p doped amorphous silicon according to the present invention
- Fig. 4b shows the optical transmission of incident radiation power being transmitted through a first semiconductor layer p doped amorphous silicon carbide according to the present invention
- Fig. 4c shows the optical transmission ratio of radiation with wavelengths of 600 nm and 400 nm that are transmitted through semiconductor layers with different optical bandgaps according to the present invention
- Fig. 5 is an illustration of PN type photodiode according to the present invention
- Fig. 6 is a principal sketch of a detecting apparatus capable of detecting the presence in a sample of a target molecule
- Fig. 7 is a flow-chart of a method according to the invention.
- Fig. 1 is an illustration of a fluorescent detection system where a sample or analyte 110 of biological material, placed on some plate 111 or in a container 111, is illuminated with an illumination beam 120. Emitted radiation in the form of scattered, reflected, diffracted, luminescent and/or fluorescent radiation 130 from the sample 110 and the plate 111 is detected by the detector 140.
- the sample 110 contains target molecules that have reacted with probe molecules so that the targets bonds to the probes.
- the probe molecules may have been provided on the plate 111 , so that the probes stick to the plate 111, prior to applying the sample 110 to the plate 111.
- target molecule and probe molecule pairs are antibody-antigen pairs, cell-antibody combinations, strands of DNA pairs, strands of RNA pairs, antibody-antigen pairs and receptor-ligands pairs.
- the target molecules, or the probe molecules can be provided or conjugated with labeling agents having luminescent or fluorescent properties. Accordingly, if the target molecules match the probe molecules, the target molecules will bond to the probe molecules. By washing away any non-reacted target molecules, so that only reacted target-probe pairs remains (assuming that the sample contained targets capable of bonding to the stuck probes), the presence, the absence, and optionally the quantity, of target molecules can be verified by detecting the luminescent or fluorescent emitted radiation from the labeling agents.
- the probes can be provided or conjugated with labeling agents having luminescent or fluorescent properties. The labeling agents attached to the probes have the property to emit fluorescent radiation only when the corresponding probes have reacted with matching targets.
- the emitted radiation 130 contains radiation in the form of fluorescent radiation originating from the labeled agents. However, the emitted radiation 130 also contains radiation in the form in of scattered, reflected and/or diffracted radiation.
- Part of the illumination beam 120 is absorbed by the labeling agents and re-emitted as radiation having a wavelength different from the wavelength of the illumination beam 120 due to fluorescence.
- Other part of the illumination beam 120 causes scattering, reflection, diffraction for instance from the plate or container 111 or from other parts of the biological sample 110.
- the emitted radiation 130 will contain radiation having a first spectral distribution Wi primarily due to scattering, reflection and diffraction, and the emitted light 130 will also contain light having a second spectral distribution Wf due to fluorescence.
- first spectral distribution Wi primarily due to scattering, reflection and diffraction
- Wf second spectral distribution
- the first spectral distribution Wi may be equal to, or correspond to, the spectral distribution Wib of the illumination beam 120. Due to absorption of light in the sample 110 and the plate 111 or container 111 the first spectral distribution Wi may differ from the spectral distribution Wib of the illumination beam 120. However, the spectral distribution Wib of the illumination beam 120 can be said to correspond to the first spectral distribution Wi or vice versa.
- the labeling agents have the capability of absorbing incident radiation from the illumination beam 120 having the spectral distribution Wib, and subsequently, in response to absorbing light, emitting light having the second spectral distribution Wf.
- the emitted radiation 130 contains radiation having both the first spectral distribution Wi and the second spectral distribution Wf.
- the spectral shift between the spectral distribution Wib of the illumination beam 120 and the second spectral distribution Wf is caused by the fluorescent properties of the labeling agents.
- the spectral shift is also referred to as the Stokes shift.
- the labeling agents are characterized by a wavelength interval in which the labeling agents are most efficiently excited so that they will respond with a fluorescent emission. Accordingly, the labeling agents are most efficiently excited when the spectral distribution Wib of the illumination beam 120 corresponds to the wavelength interval in which the labeling agents are most efficiently excited.
- the fluorescent emission generates the scattered radiation having the second spectral distribution Wf.
- the labeling agents may for instance be excitable in a wavelength interval including a wavelength of 400 nm. If the labeling agent has a spectral shift of for example 200 nm, the labeling agent will respond with a fluorescent emission having a second spectral distribution located in the vicinity of 600 nm when the labeling agent is illuminated with radiation having a spectral distribution with a center wavelength of approximately 400 nm.
- the center wavelength of the spectral distribution may for instance be understood as the wavelength where the radiation of the spectral distribution has the largest intensity.
- Quantum dots can be either metal of semiconductor nanoparticles, where the particle diameter is so small that the effect of quantum confinement gives rise to unique optical and electronics properties that are not available and electronic properties that are not available in either discrete atoms or in bulk solids. Quantum dots have the advantage of a broadband absorption spectrum, in contrast to e.g. fluorophores. The absorption of a photon with energy above the bandgap energy results in the creation of an electron-hole pair (or exciton).
- the absorption has an increased probability at higher energy (i.e., shorter wavelengths) and therefore results in a broadband absorption spectrum.
- the radiative recombination of an exciton leads to the emission of a photon in a narrow symmetric energy band.
- the long life time of the exciton (usually larger than 10 ns) and the narrow emission spectrum of quantum dots are advantageous over e.g. fluorophores.
- quantum dots there exists a large number of types of quantum dots; for instance InP quantum dots that are tuneable to emit wavelengths anywhere below 915 nm, silicon quantum dots, quantum dots synthesized from semiconductor materials such as CdS, CdSe, and CdTe (II-VI materials); InP and InAs (III-V materials); PbSe (IV-IV materials).
- the types of labeling agents are not limited to those types mentioned above and, therefore, other types of luminescent agents may equally be used for labeling samples 110.
- the list of quantum dots are not limited to those mentioned above, since quantum dots synthesized from other materials may equally be used.
- the labeling agent should not necessarily be understood as only comprising luminescent or fluorescent agents, such as quantum dots.
- the luminescent agents of the labeling agent may be interfaced with tags that are capable of binding to molecules of the sample 110.
- tags comprise recognition moieties, ligands, and charged adapter molecules that interface with the luminescent or fluorescent agents via electrostatic interactions.
- Other conjugation method comprise covalent attachment and thiol-exchange reaction.
- An example of how to conjugate biomolecules to quantum dots comprises a 50 ⁇ l quantum dot solution (2 ⁇ M), 30 ⁇ l EDC (100 mM), 30 ⁇ l sNHS (100 mM) and 90 ⁇ l protein (15 ⁇ M), followed by incubation for 2 hours and subsequent purification with a spinfilter.
- Fig. 2 is an illustration of a PIN photodiode 200 comprising a first semiconductor layer 211 doped with a first type of impurities, an intrinsic (un-doped) semiconductor layer 212 and a second semiconductor layer 213 doped with a second type of impurities.
- the first semiconductor layer 211 When the first semiconductor layer 211 is doped with an acceptor impurity having less electrons than are needed to bond it to the semiconductor material, the first semiconductor layer 211 is referred to as a p doped layer, because the acceptor impurity can accept one or more electrons from the valence band. Thus, the acceptor impurity becomes a negative ion, and a free hole is generated in the valence band.
- the second semiconductor layer 213 When the second semiconductor layer 213 is doped with a donor impurity having more valence electrons than are needed to bond it to the semiconductor material, the second semiconductor layer 213 is referred to as an n doped layer.
- the donor impurity becomes a positive ion and a free electron is generated in the conduction band.
- the intrinsic layer 212 contains no net acceptor or donor impurities, and therefore has no free holes in the valence band or free electrons in the conduction band. This makes it electrically a highly resistive material.
- the top of the valence band and the bottom of the conduction band are separated in energy by the so-called bandgap, Eg.
- bandgap In crystalline semiconductors this is a region of energies which are forbidden, that is to say that electrons may not have energies which reside within this the band gap.
- amorphous semiconductors there is a continuous density of states in the band gap but the density of states is very small, typically five or six orders of magnitude less than at the band edges.
- a photon or radiation may be absorbed in any of the first semiconductor layer 211, the intrinsic layer 212 or the second semiconductor layer 213.
- the electron-hole pair is formed in a region with no or little electric field then the electron and hole will tend to remain in close spatial proximity and recombine, giving no useful signal to a sensor. If they are generated in a region with strong electrical field then they will have a good chance of separating before they can recombine and being extracted at the electrodes to contribute to the detector signal.
- the electric field can be applied externally or be the result of band bending in the intrinsic layer 212 due to electrical contact between the doped regions and the intrinsic silicon. Electron-hole pairs generated in the heavily doped regions, such as the n and p regions of the device do not produce appreciable current.
- n regions In the case of n regions, this is because the conduction band already contains a high density of electrons donated by the impurity ions, and one of these recombines with the hole very rapidly, thus canceling out the pair generation. Additionally, the field in the n region is very low, because it is highly conducting, and so the force acting to move the hole toward the wire before it recombines is very small. Likewise, in the p region a high density of holes produces rapid recombination of the electron generated by the photon. However, in the intrinsic region there are no free carriers to recombine the electron-hole pair, and carrier separation is swift because the material is less conducting than the doped regions and therefore has a higher field gradient.
- the free electron 241 is able to migrate to the n doped layer and the free hole 242 is able to migrate to the p doped layer where they are collected and then pass out through the wires 221 and 222 as a current I, which direction is indicated by the arrow 223.
- the photodiode is arranged so that the incident radiation 231 and 232 being emitted from the sample 110 of biological material is impinging the top face 214 of the p doped layer 211. Accordingly, the top face 214 may be adapted to receive incident radiation.
- An antireflection coating 245 may also be applied on the top face 214 of the p layer. The antireflection coating 245 is capable of increasing the amount of incident radiation that is transmitted into the p doped layer. The antireflection coating is optional and need not be provided on the top face 214 of the p layer.
- the incident radiation 231 illustrates incident radiation having the first spectral distribution Wi and the incident radiation 232 illustrates radiation having the second spectral distribution Wf. Due to the difference in wavelengths of the first and second spectral distributions, and due to a wavelength dependency of the absorption properties of the p, n and intrinsic layers of the photodiode, different wavelengths will be transmitted to different layers and different depths within the layers of the photodiode. As illustrated in Fig. 2, the incident radiation 231 having the first spectral distribution Wi (for instance towards the blue end of the spectrum) will be fully absorbed, or at least substantial fully absorbed, in the p layer 211.
- the incident radiation 232 having the second spectral distribution Wf (for instance towards the red end of the spectrum) will be transmitted through the p layer and into the intrinsic layer.
- the incident radiation 232 will be partly absorbed in the p layer, while the remaining radiation 232 will be transmitted into the intrinsic layer 212 where it will be absorbed.
- the percentage of absorption in the p layer of incident radiations 231 and 232 having first and second spectral distributions depends on the thickness Tp of the p layer and the wavelengths of the first and second spectral distributions, Wi and Wf.
- the semiconductor layers 211-213 of the photodiode 200 can be manufactured for instance by depositing amorphous silicon by Plasma Enhanced Chemical Vapour Deposition (PECVD).
- PECVD Plasma Enhanced Chemical Vapour Deposition
- the deposition rate for producing amorphous silicon layers 211-213 of the photodiode 200 can for instance vary between 10 nm/min and 100 nm/min.
- the electrical contact between the wires 221-222 and the first and second semiconductor layers 211 and 213 may be provided with a metallic ring contract having a center aperture or by depositing a transparent conducting material on the faces, e.g. the top face 214.
- the transparent conducting material may be Indium Tin Oxide.
- Fig. 3 shows graphs showing the relation between the thickness Tp of the p layer 211 and the wavelength W of the incident radiation for different percentages of absorbed radiation in the p layer.
- the graphs in Fig. 3 are representative for p layers made of p-doped amorphous silicon, a-Si.
- the abscissa shows the wavelength W of the incident light and the ordinate shows the thickness of the p layer.
- the three curves labeled with percentages 50%, 90% and 99%, show the thicknesses Tp, where 50%, 90% and 99% of the incident radiation has been absorbed, as a function of wavelength W.
- absorption in the p layer does not contribute significantly to the photocurrent.
- incident radiation having for instance a wavelength of 400 nm
- this incident radiation in practice has a spectral distribution corresponding to a wavelength of 400 nm. That is, for instance, a peak amplitude, an average spectral value or a center value of the spectral distribution may be close to, or equal to a wavelength of 400 nm.
- incident radiation having a particular radiation will be completely absorbed, or at least substantially absorbed within a volume of the first semiconductor layer, for instance the p layer 211.
- Fig. 3 it is possible to estimate a suitable thickness of the first semiconductor layer 211, so that the first semiconductor layer is capable of absorbing incident radiation of a particular wavelength.
- the incident radiation having a first spectral distribution corresponding to a wavelength of e.g. 400 nm then Fig. 3 shows that a thickness Tp greater than 100 nm will cause absorption of at least 99%.
- a thickness greater than 200 nm will cause even greater absorption
- a thickness greater than 300 nm is likely to cause absorption greater than 99.9%.
- the first semiconductor layer 211 should capable of absorbing at least 80 %, preferably at least 90 % or more preferred at least 99 % of the incident radiation having the first spectral distribution. This will ensure that radiation having the first spectral distribution, e.g. 400 nm, will be sufficiently absorbed, while radiation having the second spectral distribution will be sufficiently transmitted into the intrinsic layer 212.
- the sample 110 of biological material has been labeled with a labeling agent capable of effectively absorbing radiation from the illumination beam 120 having a spectral distribution Wib corresponding to a wavelength of 405 nm.
- the labeling agent has a spectral shift, or Stokes shift, of approximately 200 nm so that the labeling agent emits radiation having a second spectral distribution corresponding to a wavelength of approximately 600 nm. If the first semiconductor layer has a thickness of, for instance 300 nm, then only the emitted radiation having a wavelength of 600 nm will be detected since the radiation having the wavelength of 405 nm will be absorbed in the first semiconductor layer.
- the incident radiation having a wavelength of 405 nm has a larger intensity compared to the incident radiation having a wavelength of 600 nm, the 405 nm radiation will not disturb the detection of the 600 nm radiation. Accordingly, the incident radiation having a second spectral distribution corresponding to the 600 nm wavelength, can be detected with high resolution.
- the wavelength or the center wavelength of the spectral distribution of the incident radiation of the illumination beam 120 may correspond to blue or violet-blue colors having wavelengths of 350nm, 375 nm, 473 nm, 405 nm, 442 nm and 490 nm, which wavelengths can be generated by lasers, semiconductor lasers or light emitting diodes. Also center wavelengths of the spectral distribution of the incident radiation corresponding to ultra violet or violet colors, having wavelengths in the range from 380 nm down to 200 nm or even down to 10 nm can be used for illumination of the sample 110.
- Such wavelengths in the range from 380 nm down to 200 nm, for instance 262 nm, 266 nm, 349 nm, 351 nm or 355 nm, can be generated by uv lasers, uv semiconductor laser or uv light emitting diodes. Greater wavelengths in the green, red and infra-red color regions, having wavelengths from 500 nm to 830 nm and possible up to 1555 nm may also be used to excite the labeling agents.
- the illumination source generating the illumination beam 120 may be a semiconductor laser, a gas laser, a discharge lamp or a light emitting diode. The list of illumination sources is not exhaustive and other illumination sources may equally be used.
- the photodiode 200 is capable of detecting incident low- intensity radiation being mixed with incident high- intensity radiation, where the low-intensity radiation has a spectral distribution that is spectrally shifted from the spectral distribution of the high- intensity radiation.
- the photodiode has spectral filtering capabilities so that the photodiode is capable of filtering out radiation having a particular spectral distribution.
- the photodiode 200 is capable of performing optical filtering corresponding to such optical filters.
- a simple and cheap photo detector is achieved, because no additional optical filters are required and no mounting of such optical filters is required.
- a simple, compact photo and cheap photo detector has been achieved by utilizing the absorbing capabilities of the first semiconductor layer 211.
- the first semiconductor layer 211, the intrinsic layer 212 and the second semiconductor layer 213 can be made of different semiconductor materials; for instance amorphous silicon (a-Si), amorphous silicon carbide (a-SiC), microcrystalline Si, materials used in the plastic/polymeric electronic technology, and crystalline silicon known from traditional crystalline technology used in production of integrated circuits. Also, low temperature polySi produced by, for instance, laser annealing of amorphous silicon may be used for the semiconductor layers.
- the choices of semiconductor materials is not limited to the above-mentioned materials, for instance other amorphous silicon alloys could be used.
- the first semiconductor layer 211 can be made of material that is different from the material used for the second semiconductor layer 213.
- the materials used for doping the first semiconductor layer 211 and the second semiconductor layer 213 can be acceptor and donor impurities respectively, from groups 3 and 5 of the periodic table, again respectively.
- the most often used acceptor dopants are B, Al, Ga and In, and the most often used donor dopants are P, As and Sb. These are most readily introduced in to the amorphous silicon from the gas phase during deposition, for example by adding diborane or phosphine gas in to the PECVD reactor. Alternatively, doping is sometimes achieved by solid state diffusion, for example from an Al electrode in contact with the amorphous silicon.
- the ratio of radiation powers, of incident radiation having a first spectral distribution and incident radiation having a second spectral distribution, being transmitted through the first semiconductor layer 211 can be adjusted by selection of the material used in the first semiconductor layer.
- Fig. 4a shows the optical transmission Tr of incident radiation power being transmitted through a first semiconductor layer 211 having a thickness Tp for 400 nm incident radiation and 600 nm incident radiation.
- the material of the first semiconductor layer 211 is p doped amorphous silicon (p a-Si), which typically has an optical bandgap, Eg of 1.6-1.65 eV corresponding to a radiation wavelength of approximately 775 nm.
- Fig. 4b shows similar graphs where the first semiconductor material is p doped amorphous silicon carbide (p a-SiC), which typically has an optical bandgap, Eg of 1.9 eV corresponding to a radiation wavelength of approximately 650 nm.
- Fig. 4b shows the optical transmission Tr of incident radiation power being transmitted through a first semiconductor layer 211 having thickness Tp, for 400 nm and 600 nm incident radiation.
- the optical transmissions Tr are greater in Fig. 4b than in Fig. 4a for equal thicknesses Tp.
- the optical transmission Tr for 600 nm radiation decreases more rapidly, as function of thicknesses Tp, in the a-Si material as compared to the a-SiC material. Therefore, the ratio of transmitted 600 nm radiation and transmitted 400 nm radiation is greater in p doped amorphous silicon carbide (p a-SiC) than p doped amorphous silicon (p a-Si).
- p doped amorphous silicon carbide may be an preferred choice for the first semiconductor layer 211.
- Fig. 4c shows the optical transmission ratio Tr(600)/Tr(400) of radiation with wavelengths of 600 nm and 400 nm that are transmitted through semiconductor layers with optical bandgaps, Eg, of 1.6 eV and 1.9 eV as a function the layer thickness Tp.
- Eg optical bandgaps
- the curve labeled with Eg 1.6 eV gives the optical transmission ratio Tr(600)/Tr(400) through a layer of amorphous silicon
- the curve labeled with Eg 1.9 eV gives the optical transmission ratio Tr(600)/Tr(400) through a layer of amorphous silicon carbide.
- the optical transmission ratio Tr(600)/Tr(400) increases more rapidly for a first semiconductor layer of amorphous silicon carbide than amorphous silicon.
- the spectral shift or Stokes shift is approximately 200 nm.
- the ratio of a transmitted radiation having second and first spectral distributions will decrease.
- the optical transmission ratio Tr(500)/Tr(400) will be smaller than the optical transmission ratio Tr(600)/Tr(400) for a given semiconductor material and a given thickness Tp.
- the difference in the optical transmissions of incident radiations having the first and second spectral distributions will provide sufficient filtering effect to filter out the incident radiation having the first spectral distribution so that the incident radiation having the second spectral distribution is detectable with sufficient high resolution.
- the spectral shift between the first spectral distribution and the second spectral distribution is at least e.g. 100 nm the difference in the optical transmissions of incident radiations having the first and second spectral distributions will provide even more filtering effect so that the incident radiation having the second spectral distribution is detectable with even higher resolution. Consequently, if the spectral shift is at least 200 nm the filtering effect will be even more pronounced so that the incident radiation having the second spectral distribution is detectable with very high resolution.
- the incident radiation 231 and 232 is incident on a first semiconductor layer 211 which is p-doped.
- a diode is referred to as a PIN diode.
- the first semiconductor layer 211 can be an n doped semiconductor layer and the second semiconductor layer 213 can be a p doped semiconductor layer.
- the absorption properties of n doped semiconductor layer typically are different than a p doped semiconductor layer of the same semiconductor material, e.g. a-Si
- the absorption properties of p doped semiconductor material as described in connection with Figs. 2, 3, 4a, 4b and 4c are also applicable to n doped semiconductor material. Accordingly, the detailed description of the absorbing properties of a semiconductor layer of n-doped semiconductor material will be omitted.
- Fig. 5 is an illustration of PN type photodiode 500.
- the PN type photodiode 500 differs from the PIN diode illustrated in Fig. 2 mainly by having a depletion layer 512 instead of an intrinsic layer 212. Accordingly, features common for the photodiodes in Fig. 2 and Fig. 5 are assigned identical reference signs and, therefore, a detailed description of features of the PN photodiode in Fig. 5 which are identical with features of the PIN photodiode in Fig. 2 will be omitted.
- both the PN type photodiode 500 and the PIN type photodiode 200 can be said to have a third semiconductor region 212,515 layer between the first semiconductor layer 211,511 and the second semiconductor layer 213,513.
- the PN photodiode 500 comprises a first semiconductor layer 511 made of p doped semiconductor material, and a second semiconductor layer 513 made of n doped semiconductor material.
- the incident radiation 231 and 232 impinges directly on the top face 214 of the p doped semiconductor layer, or alternatively the incident radiation 231 and 232 may be transmitted through the antireflection coating 245 before the incident radiation impinges the top face 214.
- the p doped semiconductor layer 511 is brought directly into electrical contact with the n doped semiconductor layer 513.
- a third semiconductor region 512 is created which extends into both the p doped layer 511 and the n doped layer 512.
- the third semiconductor region 512 will be referred to as comprised by a part of the first semiconductor layer and a part of the second semiconductor layer.
- the third semiconductor region 512 is referred to as the depletion layer since this layer is depleted from free electrons and holes.
- a photon of the incident radiation 231 enters the third semiconductor region 512, that photon will generate a free electron 542 and a free hole 541, given that the photon has sufficient energy.
- the free electron 541 will travel towards and into the n doped second semiconductor layer 513, and the hole 542 will travel towards and into the p doped first semiconductor layer 511.
- the incident radiation 231 will generate a flow of free electrons and holes that will create a detectable current I, having the direction 213.
- the p doped first semiconductor layer 511 and the n doped second semiconductor layer 513 of the PN photodiode in Fig. 5 may be reversed to form a NP photodiode where the n doped layer becomes the first semiconductor layer 511 and the p doped layer becomes the second semiconductor layer 513.
- the incident radiation will impinge a top face 214 of the n doped semiconductor layer.
- Fig. 6 is a principal sketch of a detecting apparatus 600 capable of detecting the presence in a sample 620,110 of a biological substance.
- the detecting apparatus 600 may also be referred to as a micro total analysis system (micro-tas), a lab-on-a-chip or a molecular diagnostic system (MDx).
- the detecting apparatus comprises a processing device 640.
- the processing device may be a transparent container that is provided with e.g. a hole for supplying the container with the labeled sample 620 comprising for instance species, molecules, antigens, antibodies, proteins, cells, tissue sections, DNA, blood and urine of the biological substance that has been labeled with labeling agents having luminescent or fluorescent properties.
- the processing device 640 has been provided with probe molecules that stick to e.g. the bottom surface adjacent to the photodiode 630,200. Accordingly, the labeled target molecules of the sample 620 can react with the probe molecules that have previously been applied to the processing device. Subsequently, any non-reacted target molecules can be washed away, so the sample 620 only, or at least primarily, contains bonded target-probe pairs having labeling agents connected to them.
- any molecule of the substances comprising molecules, antigens, antibodies, proteins, cells, tissue sections, DNA, blood and urine may have the function as a target molecule.
- an antigen may be used as a target and an antibody may be used as a probe; or opposite an antibody may be used as a target and an antigen may be used as a probe.
- the detection apparatus may be used for instance as DNA microarrays, or immunoassays.
- the detection apparatus 600 also comprises a radiation source 610, for instance a laser, a semiconductor laser, or a light emitting diode.
- the radiation source is capable of generating an illumination beam 611 having a spectral distribution Wib corresponding to the first spectral distribution.
- the illumination beam 611 is transmitted through the transparent container 640 so that the illumination beam illuminates the sample 620.
- the emission of radiation 621 may be caused by scattering, diffraction, refraction, reflection and emission of fluorescent radiation from the labeling agents.
- the emitted radiation 621 is transmitted as incident radiation, comprising the first and second spectral distributions, into the photodiode 630,200 for detection of radiation having the second spectral distribution.
- the photodiode 630,200 generates a photocurrent I corresponding to the radiation having the second spectral distribution.
- the photocurrent I is provided for further analysis at the terminals 631.
- the photocurrent may be analyzed by a computer or processing unit provided in the detection apparatus 600.
- the presence or absence in the sample 620 of particular biological matters such as, AIDS, drugs and viruses can be determined.
- the detection apparatus may also be arranged so that the processing device 640 is capable of processing the sample of a biological substance by labeling molecules of the sample 620. This can be achieved by providing the processing device with labeling agents in solid or fluid form. Accordingly, a sample 620 of the biological substance, which has not been labeled with labeling agents, can be injected into the processing device 640, so that the labeling agents that are made available by the processing device 640 will label species/molecules/antigens of the injected sample 620.
- the detection apparatus 600 can be arranged for operating with labeling agents selected from the group comprising: quantum dots, fluorophores, chromophores, dyes, luminescent nano-particles, nanotubes, gold particles and beads.
- the sample containing labeled or un-labeled molecules of the biological substance being supplied to the processing device 640 may be different organic materials such as cells, tissue sections, DNA, protein, blood, urine.
- the direction of the illumination beam 611 is perpendicular to the normal of the surface of the first semiconductor layer 211.
- other directions of the illumination beam 611, than the perpendicular direction can also be used in the detection apparatus.
- the detection apparatus 600 may comprise further processing devices, than the processing device 640, or alternatively other functions may be provided in the processing device 640.
- processing devices for amplifying a concentration of DNA by Polymerase Chain Reaction, for creating a flow of the sample 620 by use of a micro pump, separation of the sample 620 by use of electrophoresis and cell lysis for extraction of DNA may be used.
- the detection apparatus 500 may comprise micro fluidic channels for processing the sample 620,110 as well as devices for washing away non-reacted target molecules.
- the sample 620,110 can be labeled with different labeling agents having different spectral shifts or Stokes shifts.
- labeling agents having distinct spectral shifts of 50 nm, 100 nm, 150 nm and 200 nm may be used for labeling the sample 620.
- the labeling agents having spectral shifts of 50 nm can be connected or conjugated to a first type of molecules of the sample 110.
- Other labeling agents having spectral shifts of 100 nm can be connected or conjugated with a second type of molecules of the sample 620.
- the other labeling agents can be conjugated with other molecules.
- a first type of photodiode 200 can have a first semiconductor layer 211 having a thickness that absorbs wavelengths up to e.g. 430 nm, so that all four spectral distributions are detected.
- a second type of photodiode 200 can have a first semiconductor layer 211 having a thickness that absorbs wavelengths up to e.g.
- the third type of photodiode 200 can have a first semiconductor layer 211 having a thickness that absorbs wavelengths up to e.g. 530 nm, so that the remaining two spectral distributions (550 nm and 600 nm) are detected.
- the fourth type of photodiode 200 can have a first semiconductor layer having a thickness so that only radiation having a spectral distribution with a center wavelength of 600 nm is detected.
- Fig. 7 is a flow chart of a method according to the invention. The method for detecting a target in a sample of a biological substance comprises the steps of:
- S 1 providing a detection apparatus with probe molecules for bonding with target molecules, wherein the target molecules or probe molecules are labeled with labeling agents having luminescent properties, wherein said labeling agents emits radiation having a second spectral distribution when illuminated with radiation having a spectral distribution corresponding to the first spectral distribution,
- S2 providing the sample containing target molecules to the detection apparatus for bonding with the probe molecules
- S3 illuminating the sample with radiation having a spectral distribution corresponding to the first spectral distribution
- S4 receiving emitted radiation from the sample by using a photodiode according to a first aspect of the invention, said emitted radiation comprising the first spectral distribution and the second spectral distribution.
- luminescent radiation this should be understood as including, but not limited to: fluorescence, electroluminescence, phosphorescence, reflections and diffractions.
- Emitted radiation should be understood as including, but not limited to scattered, reflected, diffracted, luminescent and/or fluorescent radiation.
- a reference to a molecule should equally be understood as a macro-molecule, a group of connected molecules, and fractions of molecules.
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Abstract
Description
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Priority Applications (4)
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JP2009520087A JP2009545131A (en) | 2006-07-21 | 2007-07-05 | Photodiodes for detection in molecular diagnostics |
EP07825889A EP2047522A2 (en) | 2006-07-21 | 2007-07-05 | A photodiode for detection within molecular diagnostics |
US12/374,000 US8399855B2 (en) | 2006-07-21 | 2007-07-05 | Photodiode for detection within molecular diagnostics |
CN2007800275820A CN101490855B (en) | 2006-07-21 | 2007-07-05 | A photodiode for detection within molecular diagnostics, detecting device and method |
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EP06117619.4 | 2006-07-21 | ||
EP06117619 | 2006-07-21 |
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US (1) | US8399855B2 (en) |
EP (1) | EP2047522A2 (en) |
JP (2) | JP2009545131A (en) |
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JP2010272577A (en) * | 2009-05-19 | 2010-12-02 | Takehisa Sasaki | Radiation detecting element and radiation detector |
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CN109154551B (en) * | 2015-12-30 | 2021-05-14 | 生物辐射实验室股份有限公司 | Detection and signal processing system for particle assays |
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FR2946433A1 (en) * | 2009-06-05 | 2010-12-10 | Ecole Polytechnique Dgar | USE OF AN AMORPHOUS SILICON LAYER AND ANALYSIS METHOD |
EP2270477A1 (en) * | 2009-07-03 | 2011-01-05 | Nxp B.V. | Illumination detection system and method |
WO2011001409A1 (en) * | 2009-07-03 | 2011-01-06 | Nxp B.V. | Illumination detection system and method |
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EP2047522A2 (en) | 2009-04-15 |
JP2009545131A (en) | 2009-12-17 |
CN101490855A (en) | 2009-07-22 |
CN101490855B (en) | 2012-09-19 |
US8399855B2 (en) | 2013-03-19 |
WO2008012705A3 (en) | 2008-08-14 |
US20090250630A1 (en) | 2009-10-08 |
JP2014132265A (en) | 2014-07-17 |
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