The invention relates to a method for providing a proteinaceous coating on a medical implant, comprising the steps of: submersing the implant in a first aqueous solution comprising a protein and magnesium, calcium and phosphate ions through which a gaseous weak acid is passed; degassing the solution; allowing a coating to precipitate onto the implant; submersing the coated implant in a second solution to redissolve the magnesium, calcium and phosphate ions and to obtain the proteinaceous coating.

The invention relates to the field of medical implants. More in particular, the invention relates to a coating which improved the biocompatibility and bone-bonding properties of medical implants, such as orthopedic and dental prostheses.
Recently, a biomimetic coating has been developed for coating medical implants with ceramic materials, such as bone-like hydroxyapatite. This technology has been disclosed in European patent application 98203085.0 and comprises soaking an implant material, e.g. a scaffold for tissue engineering bone, into a super saturated calcium phosphate solution resembling a physiological fluid. A calcium phosphate layer uniformly precipitates on the implant surface under modulated nucleation and crystal growth conditions. This method mimics the way hydroxyapatite bone crystals are formed in the body. Considering the physiological conditions under which the biomimetic coating is grown from a fluid at body temperature, biologically active agents, such as antibiotics, can be coprecipitated.
In EP 0 806 212, an implantable coated device is disclosed that comprises a calcium phosphate layer, in which a biologically active substance may be incorporated. The coating comprising calcium phosphate and a growth factor can give rise to an enhancement of bone formation. For the preparation of the coating the surface of the device needs to have a roughness(Ra value) 10-1,000 nm.
WO 97/41273 describes a process for coating a metallic or ceramic substrate by heating a certain mineral solution, in which the substrate is immersed, to a high temperature until the pH is at least 8, after which deposition of crystalline carbonated hydroxyappetite is on the substrate is induced. Such a coating is reported to be osteoinductive, but the incorporation of bioactive agents is not disclosed. It is unlikely that the process would be suitable for such purpose, since the combination of a high temperature and a high pH, would have a detrimental effect on the thermosensitive bioactive agents.
Many mineralized tissues in living organisms are composed of crystals formed under well-controlled conditions. Proteins are key participants in the control process. Some proteins envelop the individual crystals, whereas others are occluded inside the crystals. How these proteins become occluded inside a crystal and what their role is in the crystallization process and in the determination of the properties of the crystal still remains unclear.
The present invention seeks to find a way of using the expected controlling function of proteins in mineralization processes. In particular, it is an object of the invention to find a way of using a protein to induce mineralization, calcification and/or the formation of bone tissue on a medical implant.
These objects, as well as other objects of the invention that will become clear from the present description, have been achieved by virtue of a proteinaceous coating to the implant which is applied thereto in a specific manner. Accordingly, the invention relates specifically to a method for providing a proteinaceous coating on a medical implant, comprising the steps of:
submersing the implant in a first aqueous solution comprising a protein and magnesium, calcium and phosphate ions through which a gaseous weak acid is passed;
degassing the solution;
allowing a coating to precipitate onto the implant;
submersing the coated implant in a second solution to redissolve the magnesium, calcium and phosphate ions and to obtain the proteinaceous coating.
Surprisingly, it has been found that a proteinaceous coating may be provided on a medical implant, which coating induces nucleation and growth of calcium phosphate crystals, both in vitro and in vivo. Although the coating itself will typically not contain any calcium phosphate material, it has been found to act as a type of template or matrix for mineralization. This advantageous property allows for the application of the medical implant to serve as a scaffold for tissue engineering bone tissue.
On the other hand, said property of course also increases the suitability of the implant for the purpose it originally had, i.e. being implanted in a patient in need of a bone substitute. The proteinaceous coating described herein can induce deposition of a variety of calcium phosphate compounds containing carbonate and others ions on the surface of an implantable device. The layers will be similar in composition and crystallinity with bone and teeth minerals and have desired bioresorbability, bone-bonding properties to improve the biological fixation of medical devices to living calcified tissue.
The proteinaceous coating may further form a composite with calcium phosphate crystals, for instance in vivo, leading to a biomimetic coating with mechanical properties superior to those of conventional ceramic coatings. It is believed that the protein may function as a reinforcement of a biomimetic coating by bonding calcium phosphate crystals together.
Furthermore, the proteinaceous coating enhances attachment of cells and improves the biocompatibility and bone-bonding properties of medical implants.
The medical implant on which a coating is applied in accordance with the invention may be of any inorganic, metallic, polymeric or organic material. The implant may be flat, dense or of a complex shape. It may have a porous, beaded or meshed ingrowth surface.
Metals, such as stainless steel, titanium, nickel, cobalt, chrome, niobium, molybdenum, zirconium, tantalum, and combinations thereof, can be coated for orthopaedic and dental applications. For example, devices used in total hip arthroplasty such as porous or non-porous acetabular cups and the proximal region of hip stems may be coated.
Ceramic materials, such as alumina and zirconia, glasses such as bioactive glasses made of CaOxe2x80x94SiO2xe2x80x94P2O5, and calcium phosphates, such as hydroxyapatite and tricalcium phosphate, may be coated.
The subject coatings can be applied to various polymers and plastics, more preferably biocompatible or bioresorbable ones like polyactive(trademark), a copolymer of polyethylene glycol and polybutylene terephtalate.
Before applying the coating, the substrates are preferably cleaned or treated to remove any surface contaminants and to promote good adhesion of the coating. Various methods for cleaning may be employed. The metallic implants may be rinsed with a degreaser, i.e. acetone, alkyl alcohols, etc. and then thoroughly rinsed with pure water.
In order to improve coating adhesion, various surface treatments may be applied to metal implants. Mechanical surface treatments, such as sand-blasting, scoring, polishing and grinding can increase surface roughness of the implants and improve the bonding strength between the coatings and substrate. For similar purposes, chemical surface treatments may be also applied to metal substrates prior to coating. Among others chemical treatments available for metals, acid etchings will be preferred by treating implantable devices with strong mineral acids, such as hydrofluoric, hydrochloric, sulfuric, nitric and perchloric acids. It may also useful to treat the metal devices with oxiding agents such as nitric acid, peroxyhalogen acids, hydroxyperoxides, or hydrogen peroxide to form a fresh metal oxide layer. After the mechanical or chemical treatment, it is necessary to rinse the implants with pure water under ultrasounds for removal of surface contaminants.
The method for coating medical implants consists of soaking medical implants into a calcifying solution comprising a protein at low temperature. This simple method is based on the finding that calcium phosphates are more soluble in mildly acidic medium than at neutral and even basic pH. This also applies at conditions which essentially do not affect the stability and activity of the protein in a harmful way. Thus, aqueous solutions of calcium and phosphate ions and a protein can be more concentrated at mildly acid than at neutral pH. In other words, calcium phosphates precipitate at neutral or basic pH while they remain soluble at mildly acidic pH from a solution having the same concentrations of salts.
An increase of pH in the solution can induce the following stages: under-saturation, super-saturation or the formation of a meta-stable state, nucleation and crystal growth. Calcium phosphate nuclei can form onto a substratexe2x80x94heterogeneous nucleationxe2x80x94when a solution has reached the super-saturation limit or the meta-stable state. At the super-saturation state, crystals can subsequently grow from metastable fluids. At higher saturation, homogeneous nucleation or precipitation in the solution is the predominant process. This invention makes use of pH changes to control the above stages and to induce the deposition of carbonated calcium phosphate layers on the surface of medical implants.
The above object can be achieved by bubbling a gaseous weak acid, preferably carbon dioxide gas, into a calcifying solution in order to decrease pH and thereby to increase the solubility of calcium phosphate salts. It is well known that natural sparkling water has a mildly acidic pH resulting from dissolved carbon dioxide gas. It is also an important feature that the pH of mineral water slowly increases to neutral or slightly basic pH during the natural release or exchange of dissolved carbon dioxide gas with air.
In a number of preferred embodiments, the bubbling of carbon dioxide gas into the calcifying solution is required. Carbon dioxide gas will dissolve in the calcifying solution and form hydrogen carbonate ions in water. The said medical implants are placed into an aqueous calcifying solution in which a gaseous weak acid, such as carbon dioxide gas, is passed through to produce a weakly acidic media. The initial pH of said calcifying solution is maintained in the range 3-7, preferably about 5.5 to 6.5 by bubbling CO2 gas. The carbon dioxide gas is introduced into the solution at a sufficient pressure to continuously generate bubbles. The pressure of CO2 gas will be in the range 0.1-10 bars, preferably within 0.5 to 1.5 bars, more preferably about 1 bar.
In a method according to the invention, the presence of magnesium, calcium and phosphate ions in the calcifying solution is essential. Particularly, the presence of magnesium has been found to be important for controlling the crystal growth of the coating during deposition from the calcifying solution. An optimum control of crystal growth leads to a uniform, strong and wear resistant coating. Particularly, the attachment of the coating to the substrate is beneficially effected by the presence of magnesium ions in the calcifying solution. A coating prepared according to the invention, preferably has crystals having a size in the submicrometer range. In a preferred embodiment, additional inhibitors of crystal growth, such as carbonate ions, may be incorporated in the calcifying solutions. If required, counter ions, like sodium and chloride might also be present to provide a constant ionic strength.
Preferably, the calcifying solution is prepared while the gaseous weak acid is bubbled through, in order to avoid precipitation. The introduction of the gas decreases the pH of the solution and allows the complete dissolution of the magnesium, calcium and phosphate, and possible other salts. Preferably, the bubbling is started at least 5 minutes before, and during, the addition of the salts. Thus, the pH is lowered to approximately 3-8, more preferably to 5.5-6.
Of course it is also possible to start the bubbling with the gaseous weak acid after the addition of the desired amounts of the salts to the solution. Once the bubbling is started, in accordance with this embodiment, it is important to ensure that the salts dissolve completely.
The calcifying solution is preferably prepared with ultra pure water and pure grade chemicals. The calcifying solution is preferably filter sterilized through a 0.2 microns filter membrane prior to use. The molar calcium to phosphorus ratio in the calcifying solution is generally within the range 1-3, more preferably between 1.5 to 2.5. The concentrations of the ions in the calcifying solution are chosen such, that in the absence of the gaseous weak acid, the solution is super-saturated or oversaturated. The molarity of the calcium source will generally be in the range 0.5-50 mM, preferably about 2.5 to 25 mM. The phosphate source will generally be from about 0.5 to 20 mM, more preferably about 1 to 10 mM. The concentration of magnesium in the calcifying solutions will usually be within the range 0.1-20 mM, more preferably about 1.5 to 10 mM. The carbonate concentration will range from 0 to 50 mM, more preferably 0 to 42 mM. The ionic strength will be within the range 0.10-2 M, more preferably in between 0.15 to 1.5 M. The calcifying solution is preferably stirred to approximately 10-1000 rpm, more usually 50 to 200 rpm. The temperature is maintained at about 5-80xc2x0 C., preferably in the range of about 5-50xc2x0 C.
The protein is preferably present in the above described calcifying solution. It may be added before, during or after the dissolution of the various ions that are desired in the coating. The concentration in which the protein is preferably present in the calcifying solution preferably lies between 0.001 and 10 g/l, more preferably between 0.01 and 1 g/l.
In principle, the present method may be carried out using any type of protein. Preferred, highly suitable proteins are electronegatively charged at the pH at which precipitation occurs. It is further preferred that the solubility of the protein is at least 1 gram per liter water at neutral pH. In addition, it is considered advantageous if the protein possesses disulfide bridges in its structure. Examples of highly suitable proteins include albumin, casein, gelatin, lysosime, fibronectin, fibrin and chitosan. In principle, any protein based on amino acids which have an isoelectric point below 7 and are negatively charged may be used. Examples of such amino acids include alanine, aspartic acid, cysteine, glutamine, glycine, isoleucine, leucine, methionine, proline, phosphorine, serine and valine. Particularly preferred proteins are synthetic proteins, such as polylysine, polyalanine, and polycysteine. Biologically active proteins, such as growth factors (e.g. BMP, FGF, TGF), may also be advantageously used.
Optionally, the proteinaceous coating may be bound to the implant covalently by making use of a coupling or linking agent. This agent should be capable of reacting with OH groups on the implant surface and with amino groups of the protein. The covalent bond will ensure a good mechanical attachment of the proteinaceous coating to the implant. The coupling agent is preferably chosen from the group of isocyanates, cyanuric acid, titanium alkoxides (Ti(OR)4), and silicon esters, such as Si(OR)2Cl2, wherein R represents an alkyl group of 1-4 carbon atoms. In order to obtain the covalent linkage, the coupling agent is simply added to the calcifying solution in an appropriate amount which will typically lie between 1 and 20 wt. %, based on the weight of the solution.
The carbon dioxide has a limited solubility in aqueous solutions. In contact with air, a carbonated aqueous solution is free of CO2 or completely degassed within few hours depending on the surface of solution in contact with air. The complete exchange of dissolved CO2 gas with atmosphere may be performed in approximately 8 to 48 hours, more preferably between 12 to 24 hours. The natural release of CO2 gas causes the pH of the remaining solution to increase. In others words, saturation in the calcifying solution can increase until the precipitation of the bioactive layers, including calcium phosphate and protein, on the surface of implantable materials occurs. Optionally, air can be bubbled through the solution to degas or aerate the solution and accelerate the escape, release or exchange of the gaseous weak acid. The initial and final pH values as well as pH changes with time depend on the amount of carbonate and phosphate salts added to the calcifying solution. The buffering capability can be adjusted to a desired pH value by adding more or less of phosphate and carbonate salts. The pH can be maintained within the desired range by introducing carbon dioxide gas. In essence, the flow of carbon dioxide can be adjusted by using an electro or selenoid valve piloted by the controller. During the natural release of CO2 gas out of the calcifying solution, the pH will increase to about 6-10, more preferably about 7.5 to 8.5 after soaking for 24 hours. The carbonated calcium phosphate layer comprising the protein will precipitate on the surface of implantable devices at a pH value of within about 6.5-7.5. The said precipitation on the surface of medical implants is related to a heterogeneous nucleation step. The carbonated calcium phosphate crystals might subsequently precipitate into the calcifying solution by a crystal growth process. In accordance with the invention, heterogeneous nucleation is favored by the energetic stabilization of nucleus on the substrate. The high density of nucleation ensures a uniform deposition of carbonated calcium phosphate crystals onto the surface of medical implants.
In a method according to the invention, it may be desired to control the pH and thereby the nucleation stage by bubbling CO2 gas for various time. The bubbling time is usually comprised between a few seconds to minutes, preferably about 1 to 600 seconds. The introduction of carbon dioxide causes a decrease of pH while the pH of calcifying solution has a tendency to increase naturally without bubbling CO2 gas. The increase of pH may be due to the natural exchange of CO2 gas with atmosphere and the buffering capability of the calcification solution. By adjusting the time and flow of CO2 gas introduced into the calcifying solution, the pH can oscillate around a value ranging from 6 to 9, more preferably the pH of the calcifying solution can be maintained between 6.5 to 7.5. This pH oscillation is correlated to the nucleation stage of carbonated calcium phosphate crystals on the surface of medical implants. A high density of nucleation is thereby provided and carbonated calcium phosphate crystals can nucleate and grow onto the surface of medical implants. Homogeneous layers comprising ceramic material and protein can uniformly deposit on the implant substrate. The total thickness of layers will preferably be within the range 0.5-100 microns, more likely 0.5 to 50 microns. While the layers are thin, usually below 5 microns, the coatings can diffract the natural light forming colored fringes ranging from blue to red colors. This diffraction of light is similar to the phenomenon that may be observed when a drop of oil is present on water. For higher thickness, the layers give a shiny gray or white coloration.
The thus obtained coating comprises both ceramic material and the protein. In accordance with the invention, the ceramic material is removed by dissolution in a second, solution to provide the objective proteinaceous coating. The conditions under which the dissolution is carried out are to be chosen such that the ceramic material substantially completely dissolves and the protein substantially completely remains coated on the surface of the medical implant. In other words, care should be taken that hydrolyzation of the protein is avoided as much as possible. Although it may be expected that a (partial) denaturation of the protein takes place during this step, this is considered not to harm the inductive properties of the coating, and may in fact even be beneficial.
The dissolution may be accomplished by using an acidic solution, such as an aqueous solution of which the pH is preferably chosen in the range of from 2 to 5, more preferably from 3 to 4. The acid used for obtaining the objective pH can in principle be any acid suitable for attaining the desired degree of acidity. Suitable acids do not adversely affect the protein. Examples are hydrogen phtalate and hydrochloric acid, which acids are preferably used in aqueous solutions of 30-70 mM.
In an other embodiment the dissolution of the ceramic material is accomplished in a solution comprising a complexing or sequestering agent to redissolve the magnesium, calcium and phosphate ions and to obtain the proteinaceous coating. The solution comprising the sequestering agent is preferably an aqueous solution of which the pH may be alkaline, neutral or acidic. The pH is preferably in the range of 2-9, more preferably in the range of 2-7 and. Most preferably the pH is in the range of 4-6, because of the better solubility of free calcium and magnesium at an acidic pH, in combination with a relatively high degree of complexation.
In principle any sequestering agent for calcium and magnesium can be used to dissolve the mineral part of the coating. A suitable sequestering agent does not adversely affect the protein. The sequestering agent may be used alone or together with one or more other sequestering agents, e.g. to optimize the complexation of the different cations in the ceramic materials.
Very good results have been achieved with ethylene diamine tetra acetate (EDTA, e.g. the sodium salt)as a sequestering agent. A highly preferred pH for this particular embodiment is in the range of 4-6.
It has been found that ceramic material can be dissolved from the coating by using a sequestering agent in a wide concentration range. A sequestering agent may be used in any concentration, up to its saturated concentration. Preferably the concentration is between 0.1 and 20 wt. %, more preferably between 1 and 10%.
Dissolution of the ceramic material by using a sequestering or complexing agent can be performed such that the protein does not significantly denaturate, which can be advantageous for particular applications.
Once the ceramic material has essentially completely been removed, the medical implant with the proteinaceous coating may be taken out of the solution in which the ceramic material has been dissolved and optionally rinsed with water or demineralized water in order to remove trace amounts of acid and/or ceramic material. The medical implant thus obtained has been found to induce mineralization, calcifications and/or formation of bone tissue in vitro and in vivo. Accordingly, the implant has an improved performance as a bone substitute in comparison with the implant without the proteinaceous coating.
It has also been found that upon exposure to a calcifying solution, recalcification of the protenaceous layer may take place in such a way that the morphology of the layer after remineralization closely resembles that of the intermediate coating, comprising protein and calcium phosphate, before the decalcification. This recalcification process is expected to take place in vivo, depending on the site of implantation. Since the layer may completely resorb the minerals, the risk for creating brittle zones in the coatings that may cause fracture, is minimized.
Furthermore, the inductive property of the coating makes the coated implant highly suitable for use as a scaffold for tissue engineering bone. In this application, cells may be seed onto the implant and cultured to form or to start forming bone tissue.
The invention will now be elucidated by the following, non-restrictive examples.


A carbon dioxide sensor including a closed chamber having as a wall substantially water-tight, carbon dioxide-permeable membrane and containing two electrodes. The chamber contains a film of de-ionized water contacting the membrane and both of the electrodes. The change in conductance of the water due to absorption of carbon dioxide is measured.

The invention relates to a sensor for the partial pressure of carbon dioxide (pCO2) in particular in vivo or ex vivo, e.g. in or on the surfaces of body tissues or organs, in blood or in the airflow from the lungs, and to a method of measuring pCO2.
Ischemia, localized diminution in blood flow, is the most prevalent cause of death in the western world. Thus for example myocardial infarction, cerebral infarction and other conditions characterised by hypoperfusion to one or more organs are major factors in mortality.
Reperfusion, reversal of ischemia, is frequently possible if an ischemia is detected in time. Thus early detection of ischemia followed by appropriate chemical treatment (e.g. with an agent such as streptokinase, urokinase or t-PA which serves to lyse thrombi or emboli) or surgical intervention can save the affected organ as well as the patient""s life.
While the heart may be monitored continuously for ischemias using an electrocardiograph (ECG), other organs may become severely ischemic and incur irreversible damage before any symptom is detected. Indeed many organs are xe2x80x9csilentxe2x80x9d when it comes to ischemia. The phenomenon of silent myocardial infarction is now well recognised. Furthermore, liver and kidney may be severely ischemic without alerting symptoms before the organ damage is irreversible.
It is known that there is a distinct correlation between pCO2 in or on the surface of an organ and the presence of an ischemia in that organ. During tissue metabolic acidosis, e.g. during the anaerobic metabolism that occurs in an ischemia in any organ or tissue, large quantities of carbon dioxide are formed. CO2 is in practical terms freely cell-membrane permeable and since in the ischemia blood flow to transport away the CO2 is absent or restricted, CO2 build up in the ischemic tissue will occur and pCO2 in or on the ischemic tissue will increase. Generally, in the healthy body, the maximum pCO2 in blood (venous blood) is 7-10 kPa and the maximum PCO2 in healthy (aerobic) tissue is some 1-6 kPa higher, although the maxima may vary from organ to organ, e.g. 8-12 kPa for kidney, 7-11 kPa for liver, 8-12 kPa for intestinal serosa, and 12-19 kPa for intestinal mucosa. Where oxygen supply falls below the critical oxygen delivery level, PC02 values measured in the tissue may rise by 3 to 10 times and the elevated PCO2 levels give a clear indication of anaerobic metabolism and hence, if appropriate, of ischemia.
Sensors for pCO2 are available: however these are generally bulky, often involve relatively complex glass electrodes, routinely do not give stable reproducible readings (i.e. suffer problems of drift), and are sufficiently expensive as to mandate reuse and thus the need to be repeatedly sterilized.
DE-A-2911343 and U.S. Pat. No. 4,324,256 disclose an electrode device for transcutaneous pCO2 measurment with a pH-sensitive measuring electrode in contact with a bicarbonate electrolyte.
There is thus a need for simple, small, and preferably disposable, sensors which can be used generally to determine pCO2, e.g. in order to detect ischemias.
We have now developed a simple sensor particularly suitable for pCO2 measurement, especially as part of a technique for monitoring for ischemias.
Viewed from one aspect therefore the invention provides a carbon dioxide sensor comprising a closed chamber having as a wall portion thereof a substantially water-tight, carbon dioxide-permeable membrane and containing two electrodes, said chamber containing a film of substantially electrolyte-free liquid capable of simultaneously contacting said membrane and both of said electrodes.
By substantially electrolyte-free, it is meant that the liquid has an osmolality no greater than that at 37xc2x0 C. of an aqueous 5 mM sodium chloride solution, preferably no more than that of a 500 xcexcM sodium chloride solution, more especially no more than that of a 10xe2x88x925 to 10xe2x88x926 M HCl solution.
Viewed from an alternative aspect the invention provides a carbon dioxide sensor comprising a first electrode, a second electrode, a carbon dioxide permeable membrane, a liquid in electrical contact with said first and second electrodes and said membrane, means for applying an alternating electrical potential to said first and second electrodes whereby to cause an alternating current in said liquid, and means for generating a signal indicative of the conductance of said liquid, wherein said liquid is reactive with carbon dioxide to alter its conductance and wherein said electrical potential has a frequency of 20 to 10000 Hz, preferably 100 to 4000 Hz.
Viewed from a still further aspect the invention provides a carbon dioxide sensor comprising a first electrode, a second electrode, a carbon dioxide permeable membrane, a liquid in electrical contact with said first and second electrodes and said membrane, and wall means which together with said membrane and said electrodes define a chamber enclosing said liquid such that in the electrical path between said electrodes through said liquid the electrical resistance of said liquid at each of said electrodes is less than in a portion of said liquid in contact with said membrane. This increased electrical resistance relative to the resistance at the electrodes may be achieved by restricting the cross sectional area of the electrical path through the liquid between the electrodes at a zone in which the liquid is in contact with the membrane, e.g. by decreasing the depth of the liquid for a part of the path between the electrodes, and/or by ensuring a relatively large area of contact between each electrode and the liquid.
Preferably the liquid in contact with the electrodes is aqueous and especially preferably it is water, substantially electrolyte-free as defined above. Other solvents that react with CO2 to increase or decrease their conductance, e.g. by the production or neutralization of ions, may likewise be used. In practice, however, deionized or distilled water with or without the addition of a strong acid (e.g. HCl) to a concentration of 0.1 to 100 xcexcM, preferably 0.5 to 50 xcexcM, more especially about 1 xcexcM, has been found to function particularly well. The function of this small addition of acid is generally to maintain the pH of the liquid at 6 or below to avoid significant contributions to conductance by hydroxyl ions and to maintain the linearity of the measurements of PCO2.
The sensors of the invention are provided with or are connectable to an electrical power source arranged to apply an alternating electrical potential across the electrodes with a frequency of 20 to 10000 Hz, preferably 50 to 4000 Hz, more especially 100 to 1200 Hz. At frequencies below 20 Hz, the sensitivity of pCO2 determination is lower due to electropolarization and moreover the instrument response time becomes overly slow, while at frequencies above 10 kHz sensitivity is again less due to stray capacitance effects.
For particularly high accuracy, the potential or current across the electrodes (and hence the resistance or conductance of the liquid between the electrodes) is determined using a lock-in amplifier set to the same frequency as that of the voltage generator.
Furthermore it is preferred to incorporate in the sensor, or in a sensor-plus-detector system, a passive high pass filter (e.g. a capacitor and a resistor) to screen out current with a frequency less than 20 Hz, preferably less than 150 Hz.
The power source may be an AC power source or alternatively a DC source in conjunction with an oscillator, i.e. a combination which together constitutes an AC power source.
The power supply is preferably such that the maximum current density through the liquid at the electrodes is no more than 50 A/m2, preferably no more than 30 A/m2, more preferably no more than 20 A/m2, in particular no more than 10 A/m2, and most preferably about 1 A/m2 or below. Higher current density values of 20 A/m2 or greater should only be used at the higher frequencies, e.g. 1-10 kHz. The smallest maximum current density is determined by detection limits, but values down to 10-8 A/m2 are usable. The smallest maximum current density however will generally be at least 0.1 xcexcA/m2.
By operating at such current densities and voltage frequencies, and by appropriate construction, the sensors of the invention can, unlike the prior art devices, determine the conductance/resistance of the liquid into which the CO2 migrates without any significant loss of accuracy arising as a result of the electropolarization of the electrodes.
Electropolarization effects are considerably reduced by increasing the surface area of the electrodes in contact with the liquid, e.g. by siting the electrodes in wells disposed away from the plane of the membrane or by using non planar electrode surfaces, e.g. rough or textured surfaces. In general therefore it is desirable to have as large a surface area of electrode: liquid contact as possible, as large a surface area of membrane:liquid contact as possible, and as shallow as possible a liquid depth over as much as possible of its area of contact with the membrane. In this way the response time is reduced, electropolarization is reduced, lower frequencies may be used and stray capacitance effects are considerably reduced.
The resistance of the liquid at the membrane and between the electrodes may be increased by the use of means to define liquid channels across the membrane between the electrodes, e.g. by disposing the membrane across or adjacent an insulating chamber wall portion in which such channels are formed, for example by etching. Likewise a porous spacer may be disposed between the membrane and the chamber wall to define the depth of the liquid.
Indeed, such spacers are important to use where, under the pressure conditions experienced in use, the membrane is sufficiently flexible and the liquid depth behind the membrane sufficiently small, for the measured conductance to vary with pressure. However, where a flexible non-CO2 permeable membrane is used, the omission of the spacer or the use of an apertured spacer which allows the membrane to deform under pressure leads to a device in which determination of conductance may be used as a means of measuring pressure, e.g. in vivo.
Thus viewed from a further aspect the invention provides a pressure sensor comprising a first electrode, a second electrode, a flexible membrane, preferably a gas impermeable membrane, and an electrically conductive liquid in contact with said electrodes and said membrane the conductance whereof is altered by pressure induced deformation of said membrane. Such a pressure sensor may be constructed and operated along the same principles as the pCO2 sensors of the invention.
The power source and the detector circuitry may, if desired, be included in the sensor of the invention. In this case, if it is desired that the sensor be wire (ie. lead) free, it will preferably also be provided with means enabling the signal to be detected remotely, e.g. a transmitter, for example a RF transmitter. In this way the sensor may be implanted, for example in an at-risk patient.
The sensors according to the invention are readily produced having a size and configuration particularly suited to measuring pCO2 (or pressure) on the surface of or in an organ, duct or tissue, e.g. brain, heart, liver, kidney, gut or muscle. This is of particular interest as it allows the functioning of the organ, duct or tissue to be monitored, e.g. during and after transplant, in intensive care, following injury, etc. and so allows early detection of ischemias.
Viewed from another aspect the invention provides a method of determining pCO2, e.g. to detect or monitor ischemias, in a human or vascularized non-human animal body (e.g. a mammal, bird or reptile), said method comprising determining a partial pressure of carbon dioxide at a site in said body using a sensor according to the invention, whereby to detect ischemias in said body. The partial pressure determined according to the method of the invention may be a quantified value or it may simply be an indication that pCO2 is above or below one or more threshold values indicative of ischemia or non-ischemia, values which may be varied according to the location of the pCO2 measurement site.
The method of the invention will generally involve determination of pCO2 in blood, on or in an organ, duct or tissue, or in the air flow from the lungs. In the latter case the pCO2 sensor may be inserted into the body or may alternatively be in a hose one end of which is inserted into the body, i.e. within the airways.
The method of the invention may involve a single measurement of pCO2 or, more preferably, may be used for continuous or repeated monitoring, especially of an at-risk patient, for example a patient in intensive care, undergoing or recovering from an organ or tissue transplant operation, assessed as having unstable angina, recovering from a coronary artery bypass operation, suffering trauma (e.g. of skeletal muscle), or suffering from hypovolemia (e.g. shock).
The comparison or threshold values for pCO2 which may be used in the method of the invention may be values detected earlier in a continuous or repeated monitoring of a particular body site using the sensor or they may be values detected for comparable body sites in the healthy, e.g. non-ischemic, body of a comparable subject (e.g. a subject of the same species and sex and similar age and weight).
The primary components of the sensor are an electrode chamber, a CO2-permeable membrane forming at least part of the wall of the electrode chamber, first and second electrodes having surfaces within said chamber (or providing internal surfaces to said chamber), and a liquid (generally substantially electrolyte-free water) in the electrode chamber in contact with the membrane and the first and second electrodes. The sensor includes or is connectable to an AC power supply, a conductance (or resistance) determining means, a signal generating means (which may be part of the determining means) and optionally a signal transmitting means. Moreover the sensor optionally includes surface attachment means by which it may be held in contact with a body surface (e.g. an organ, tissue or duct surface) or surface piercing means by the use of which it may be introduced through a body surface (e.g. an organ, tissue or duct surface).
In one embodiment of the sensor of the invention, a first of the two electrodes has a hollow cylindrical portion and the second is disposed within the hollow cylinder of the first, preferably at or near the axis thereof. The second electrode itself preferably has a solid cylindrical portion disposed within the hollow cylindrical portion of the first electrode. Where the first electrode has a hollow cylindrical portion, this can if desired form a wall of a closed electrode chamber containing liquid and the second electrode and having at least a wall portion provided by the CO2-permeable membrane; however, it is preferred that the sensor has a closed electrode chamber having a further cylindrical wall surrounding, and preferably coaxial with, the two electrodes.
The cylindrical portions of the two electrodes preferably are axially coterminous at the end facing the membrane. They may contact the membrane if it is non-conductive but preferably are slightly displaced from it, e.g. by use of a spacer which may serve to limit or prevent deformation of the membrane.
The first electrode preferably has an outer diameter of the cylindrical portion of 0.8 to 2 mm, more preferably 1.2 to 1.6 mm. The second electrode preferably has an outer diameter of the cylindrical portion of 0.2 to 0.6 mm, more preferably 0.3 to 0.5 mm. The chamber preferably is hollow cylindrical with an internal length of 0.5 to 20 mm, more preferably 5 to 12 mm, and an internal diameter of 0.8 to 2.5 mm, more preferably 1.4 to 2.0 mm.
The membrane is preferably disposed substantially perpendicular to the electrode axis and spaced away from the cylindrical ends of the electrodes, for example by 0.05 to 0.5 mm, preferably by 0.1 to 0.2 mm.
The liquid film preferably covers the membrane to a depth of 0.0005 to 2 mm, more preferably 0.001 to 0.5 mm, when the membrane is horizontal.
Where the sensor is to be used in locations where it cannot be held with the membrane horizontal, the internal depth of the chamber is preferably kept small. In this way the liquid film will fill or almost entirely fill the chamber and so contact the membrane and both electrodes irrespective of the position in which the sensor is held.
The sensor of the invention will preferably include electrical leads from the two electrodes attachable directly or indirectly to a voltage or current applicator and measurement means. Moreover where the sensor is constructed without the liquid film, the chamber will be provided with means for insertion of the liquid, e.g. a sealable inlet port or a pierceable self-sealing substrate such as a rubber stopper. The sensor, with the exception of the membrane which must be exposed at least in part, may if desired be surrounded by a protective biotolerable material, e.g. a casing or a film coating, preferably of a non-conductive material. Likewise, where the sensor is intended for continuous monitoring of blood pCO2, its surface may be coated with an anticoagulant, e.g. heparin. An anticoagulant coating may also be of advantage where the sensor is inserted into an organ and may induce clotting.
Where the sensor is constructed with the liquid film in place, the electrodes are preferably of an inert material such that the resistivity of the liquid will not change significantly with storage. Suitable materials include platinum (especially black platinum), stainless steel, silver, aluminium and carbon, particularly platinum and stainless steel (especially non-magnetic stainless steel where the sensor is to be used in imposed magnetic fields, for example within magnetic resonance imaging apparatus). In general inert electrodes which do not generate solvated ions are preferred. The thickness of the outer electrode and the diameter of the inner electrode will to a large degree depend on the strength of the electrode material used. Both electrodes are preferably of the same material to avoid a DC potential between the electrodes.
The liquid in the sensor may be any liquid capable of changing conductivity on reaction with (e.g. on dissolution therein of) carbon dioxide, e.g. a polar protic solvent capable of dissolving carbon dioxide and thereby producing ions. Water is preferred, however lower alkanols may be used. The liquid however is preferably as free as possible from dissolved ionic species and thus pure, e.g. double distilled, water is most preferred. As indicated above however, to such pure solvents it is desirable to add a small quantity of a strong acid, e.g. to maintain a pH of 6 or below. The quantity of liquid used should preferably be kept as small as possible as in this way the sensor is more rapidly responsive to external changes in pCO2. However the quantity used should preferably be preselected, i.e. so that a group of similar sensors will each contain the same quantity of liquid. In the sensor as manufactured, any gas within the chamber should preferably be essentially CO2 free, e.g. the liquid may have a nitrogen-filled head space. Before use, the sensor will preferably have been sterilised and packed in an airtight, e.g. foil, container to ensure that no accidental exposure to raised levels of CO2 occurs. Also the atmosphere inside the container preferably should be saturated with water vapour to prevent evaporation.
The membrane may be any material which is permeable to CO2, and essentially impermeable to the solvent of the liquid, any electrolyte and water. Teflon(copyright), silicone rubber, polysiloxane, or other insulating polymer films may be used, e.g. at thicknesses of 0.5 to 250 xcexcm. The thicker the membrane, in general the slower the response time of the sensor will be. However the thinner the membrane the greater the risk of non-uniformities or of perforation or other damage. In general, membranes should be thinner for pCO2 measurement in blood or in the airflow. The thicker membranes reduce capacitance effects from ions in organs. In any of the embodiments of the invention, a second (or further) CO2 permeable membrane is preferably mounted adjacent the membrane which contacts the liquid in the sensor. Between the two membranes there may be an air (or other gas) gap (optionally including a gas-permeable spacer) or more preferably a gel especially one containing a sequestering agent (e.g. a chelating agent) that serves to bind anions or cations entering the gap through the external membrane or through holes or defects therein. (In this way drift in long term measurements on organs or tissues may be reduced or avoided). Such a double membrane construction also avoids the capacitance effects of ions in organs and reduces risk of accidental inner membrane perforation and as a result the thinner membranes may be used for pCO2 measurement in organs. Conveniently however the membrane will be about 0.5 to 10 xcexcm, preferably about 1 xcexcm for blood or airflow pCO2 measurement and 1 to 50 xcexcm, preferably 2 to 40 xcexcm for organ pCO2 measurements. It will be appreciated that for detecting ischemia, a response time as long as 10 minutes may be acceptable.
The walls of the chamber of the sensor of the invention may be of any suitable material, e.g. plastics. Preferably the material should be capable of withstanding conditions normally used in sterilisation, e.g. radiation sterilization (for example using xcex3-radiation) or thermal sterilization (for example using temperatures of about 121xc2x0 C. as used in autoclave sterilisation). In the case of thermal sterilization, the liquid will generally be sterile filled into the sensor after sterilization. The walls of the chamber and the membrane may be of the same material, e.g. Teflon(copyright) machined to have self-supporting walls and a thinner gas-permeable end membrane.
In a further, preferred, embodiment the sensor of the invention comprises a CO2 permeable membrane which provides one face of a liquid containing chamber in which the liquid containing volume is defined by the membrane, a first electrode, a second electrode and insulating wall means, the wall means, electrodes and membrane defining (i) a small cross-sectional area of the liquid (across the direction of current flow) at a membrane contacting portion of the liquid, (ii) a large surface area membrane-contacting portion of the liquid and (iii) relatively large electrode:liquid contact portions. This may be achieved by placing the electrodes in wells in an insulator (which may or may not be provided with channels between the wells) with a central insulator portion which is more closely adjacent the membrane such that liquid resistance is higher in a membrane-adjacent portion of the electrical flow path than in the electrode adjacent portions. For this purpose, the electrodes may conveniently be formed as layers within a sandwich electrode:insulator construction or as wires or deposits placed in grooves or indentations in an insulator substrate.
The sensor device of the invention can thus be made small enough for insertion into a respiratory hose, into the vasculature or into or onto the surface of an organ, tissue or duct; it is cheap and simple and may have single-use application (i.e. it can be disposable) or alternatively it may be sterilised and reused. The response time to pCO2 changes is rapid (e.g. 10 minutes, preferably 5 minutes, or more preferably 30 seconds, or less) and problems of drift encountered with conventional blood gas electrodes are avoided. The device is thus well-suited for the clinical environment.
Where the sensor is to be reused, the membrane and electrodes are preferably separable to permit replacement of the liquid. Thus for example the membrane may be replaceable, e.g. taking the form of a disc disposed between the body and a sealingly engageable and removable end cap of the chamber. In this embodiment, between uses, the end cap and membrane will be removed, the solvent replaced, and the end cap and membrane disc (either as two components or an integral unit) replaced. During or after this procedure, the sensor will be sterilized. More preferably however the sensor will be a single-use, disposable device.
For in vivo measurement of pCO2 (except for in vivo blood gas measurements) no widely commercially available technique has yet been developed. Several techniques have been tried in animal experiments (ISFET electrodes, infrared absorption and others), but all of them have shortcomings. (ISFET electrodes have been used in humans but without satisfactory results). Among weaknesses are size, drifting and high cost of manufacturing. In contrast the sensors of the invention are inexpensive to produce, will have minimal drifting and with proper quality of de-ionized water, calibration may not be necessary. Using a small volume of water and preferably carbonic anhydrase, they will be fast enough for measuring end-expiratory pCO2. The sensors can be small and can be disposed in the main stream in a respirator hose. Consequently, there will be no need to suction out gas from the ventilator hoses as is now done with most techniques. This is a definite advantage, particularly in the monitoring of children whose respiratory volumes are small. Thus the sensors of the invention have the potential of being applicable for in vitro, in vivo and end-expiratory measurements of pCO2. They can both be used for ventilatory monitoring, intravascular pCO2 measurement and for detection of ischemia at the organ level.
Besides in vivo an ex vivo uses, the sensors of the invention may be used in other situations where pCO2 measurement is desired, in particular uses not associated with animate test subjects, e.g. in vitro measurements of pCO2 in gases or liquids, for example drinks or effluent gases. In further aspects the invention provides a method of determining pCO2 or pressure in such in vitro uses using sensors according to the invention.
It is especially preferred that the sensors of the invention be applied to the surface of a tissue, duct or organ of interest to determine pCO2 for that tissue, duct or organ. This is feasible since CO2 diffuses out of tissues, ducts and organs such as the heart, liver, kidney, brain, gut and muscle. For these purposes it is desirable that the sensor include surface attachment means (e.g. a flexible or perforated flange which may be sutured to the organ, tissue or duct surface; a flexible tissue-adhesive carrying flange; an adjustable clip; a flexible barb etc). In this embodiment, the electrode chamber is preferably disc-shaped with the CO2 permeable membrane on one of the faces of the disc. Such pCO2 sensors are in themselves novel and form a further aspect of the invention. Viewed from this aspect the invention provides a pCO2 sensor having a disc-shaped electrode chamber one face of which is provided at least in part by a CO2 permeable membrane, said sensor further comprising surface attachment means.
Where alternatively the sensor is to be inserted through a body surface (e.g. an organ, tissue or duct surface) it will conveniently be provided with surface piercing means, for example having the electrode chamber in the shaft of an elongate sharp-ended sensor. Such sensors are also novel and form a further aspect of the invention. Viewed from this aspect the invention provides a pCO2 sensor having an elongate body portion with sharp body surface piercing means at a first end thereof and containing spaced away from said first end an electrode chamber at least a portion of an exposed wall whereof is provided by a CO2 permeable membrane.
The sensors of the invention are relatively inexpensive and so, unlike prior art sensors, may be single-use devices. Moreover the electrode chamber can be made extremely small without difficulty (unlike the prior art glass electrode containing sensors for which miniaturization poses insuperable impedance problems).
The mechanism by which pCO2 is determined using the sensor device of the invention is straightforward. In a pure protic solvent, e.g. water, the electrical resistance is high because of the paucity of ionic species. Addition of CO2 results in formation (with water) of H+ and HCOxe2x88x923 ions and thus a reduction in the electrical resistance. Since the only factor responsible for reduction in resistance in the sensor is CO2 passing through the membrane, the change in resistance enables pCO2 to be measured. (In the pressure sensor of the invention on the other hand the change in resistance arises from the change in cross sectional area of the electrical path through the liquid due to pressure induced deformation of the membrane).
From the equilibrium constant for the H2O+CO2 to H++HCOxe2x88x923 equilibrium, CO2 concentration is equal to xcex1pCO2 (where xcex1 at 25xc2x0 C. is 0.310). The electrical conductivity for protons is GH+=349.8 S.cm2/mol, that for hydroxyls is GOHxe2x88x92=198.3 S.cm2/mol and that for bicarbonate is GHCO3xe2x88x92=44.5 S.cm2/mol. The concentrations of H+ and OHxe2x88x92 vary inversely, and the concentrations of H+ and HCO3xe2x88x92are directly proportional to pCO2. The total conductance of the solution is thus effectively proportional to pCO2 since the contribution of OHxe2x88x92 is minimal. The conductivity of the solution Gsolution is thus given by
Gsolution=xcex8H+[H+]GH++xcex8OHxe2x88x92[OHxe2x88x92]GOHxe2x88x92+xcex8HCOxe2x88x923[HCO3xe2x88x92]GHCO3xe2x88x92
where xcex8Hxe2x88x92, xcex8OHxe2x88x92 and xcex8HCO3xe2x88x92 are the activity coefficients for the three ionic species.
Table 1 below shows, by way of example, measured pCO2 and pH values and corresponding calculated values for H+, OHxe2x88x92 and HCO3xe2x88x92 concentrations showing the increase of H+ and HCO3xe2x88x92 with increasing pCO2.
The electrical conductivity is measured in the solvent film in the sensor of the invention. This can be done by applying a constant voltage (or current) to the electrodes and measuring the current (or voltage) changes which correspond to changes in conductivity as CO2 enters the solvent through the membrane. Preferably however an alternating sine wave function voltage with a constant peak value is applied and the voltage drop over the two electrodes is measured. The solution conductivity is then equal to the current passed through the electrode divided by the voltage drop over the two electrodes.

Carbon dioxide sensor and a method of determining partial pressure of carbon dioxide


Methods and systems for utilizing a database are disclosed. The methods and systems determine a key representative of a storage location of first RDF data in a NoSQL database. In addition, the methods and systems read the first RDF data in the NoSQL database using the key. The methods and systems also write second RDF data derived from the first RDF data into a second database stored in memory. The methods and systems may also modify the second RDF data, and write third RDF data derived from the modified second RDF data into the NoSQL database.

The Resource Description Framework (RDF) is a standard model for data interchange on the Internet. RDF allows for data expressions to be made in the form of triples. An RDF triple contains three components: a subject, a predicate, and an object. A subject in an RDF triple indicates what resource is described by the triple. A predicate in an RDF triple indicates characteristics of the resource, and may provide a relationship between the resource and the object of the RDF triple. For example, in the context of customer billing, the subject in an RDF triple could be an account, the predicate in the RDF triple could be an account balance, and the object in the RDF triple could be a numerical value reflecting a customer's account balance. By using this model, a database of RDF triples can be maintained that can be processed and shared across different applications. In addition, RDF databases have indices that relate resources to the triples for which the resources are subjects, predicates, or values. As such, complex queries can be made against an RDF database. However, because of the need to maintain a large number of indices and triples, RDF databases have traditionally suffered from a lack of scalability.
NoSQL databases are databases not based on the Structured Query Language (SQL). NoSQL databases can be designed to be linearly scalable by using several servers where data is distributed and replicated among the servers. Linearly scalable NoSQL databases typically access data using a primary key, which may be composed of one or more sub-keys (e.g., a row key and column key). In a key-value database, a key is used to look up a corresponding value, or "cell," that can contain data.
In order to increase flexibility, NoSQL databases are sometimes arranged as two-dimensional tabular databases that are looked up using both a row key and a column key. That is, the primary key in a two-dimensional tabular database may comprise a row key and a column key. Looking up data in a two-dimensional tabular database typically requires either access to both a row key and column key that correspond to target data, or access to one of the row and column keys combined with a requirement to scan a substantial portion of the database. However, maintaining a plurality of indices while ensuring the indices are consistent with the indexed data may be costly in terms of performance. In order to ease index maintenance, applications that utilize typical two-dimensional tabular NoSQL databases will often be limited to a small number of indices, limiting the variety of queries that can be efficiently executed. In addition, the traditional linearly scalable NoSQL databases do not permit queries that join several pieces of data from different locations. Thus, while NoSQL databases may be implemented to be linearly scalable, NoSQL databases traditionally suffer from a lack of flexibility.

Methods and systems for flexible and scalable databases


A method and system for creating an index of content without interfering with the source of the content includes an offline content indexing system that creates an index of content from an offline copy of data. The system may associate additional properties or tags with data that are not part of traditional indexing of content, such as the time the content was last available or user attributes associated with the content. Users can search the created index to locate content that is no longer available or based on the associate attributes.

Computer systems contain large amounts of data. This data includes personal data, such as financial data, customer/client/patient contact data, audio/visual data, and much more. Corporate computer systems often contain word processing documents, engineering diagrams, spreadsheets, business strategy presentations, and so on. With the proliferation of computer systems and the ease of creating content, the amount of content in an organization has expanded rapidly. Even small offices often have more information stored than any single employee can know about or locate.
Many organizations have installed content management software that actively searches for files within the organization and creates an index of the information available in each file that can be used to search for and retrieve documents based on a topic. Such content management software generally maintains on index of keywords found within the content, such as words in a document.
Creating a content index generally requires access to all of the computer systems within an organization and can put an unexpected load on already burdened systems. Some organizations defer content indexing until off hours, such as early in the morning to reduce the impact to the availability of systems. However, other operations may compete for system resources during off hours. For example, system backups are also generally scheduled for off hours. Systems may be placed in an unavailable state during times when backups are being performed, called the backup window, to prevent data from changing. For organizations with large amounts of data, any interruption, such as that from content indexing, jeopardizes the ability to complete the backup during the backup window.
Furthermore, traditional content indexing only identifies information that is currently available within the organization, and may be insufficient to find all of the data required by an organization. For example, an organization may be asked to produce files that existed during a past time period in response to a legal discovery request. Emails from five years ago or files that have been deleted or are no longer available except in offsite backup tapes may be required to answer such a request. An organization may be obligated to go through the time consuming task of retrieving all of this content and conducting a manual search for content related to the request.
There is a need for a system that overcomes the above problems, as well as providing additional benefits.
In the drawings, the same reference numbers and acronyms identify elements or acts with the same or similar functionality for ease of understanding and convenience. To easily identify the discussion of any particular element or act, the most significant digit or digits in a reference number refer to the Figure number in which that element is first introduced (e.g., element 1104 is first introduced and discussed with respect to FIG. 11).
The headings provided herein are for convenience only and do not necessarily affect the scope or meaning of the claimed invention.
Detailed Description
Overview
A method and system for creating an index of content without interfering with the source of the content including an offline content indexing system that creates an index of content from an offline copy of data is provided. In general, organizations may have a primary or production copy of source data and one or more offline or secondary copies of data. Secondary copies can be created using various storage operations such as snapshots, backups, replication, migration, and other operations. The offline content indexing system can create an index of an organization's content by examining secondary copies of the organization's data (e.g., backup files generated from routine backups performed by the organization). The offline content indexing system can index content from current secondary copies of the system as well as older offline copies that contain data that may no longer be available on the organization's network. For example, the organization may have secondary copies dating back several years that contain older data that is no longer readily available, but may still be relevant to the organization. The offline content indexing system may associate additional properties with data that are not part of traditional indexing of content, called metadata, such as the time the content was last available or user attributes associated with the content. For example, user attributes such as a project name with which a data file is associated may be stored.
Members of the organization can search the created index to locate content that is no longer readily available or based on the associated attributes. For example, a user can search for content related to a project that was cancelled a year ago. Thus, users can find additional organization data that is not available in traditional content indexing systems. Moreover, by using secondary copies, content indexing does not impact the availability of the system that is the original source of the content.
In some embodiments, members of the organization can search for content within the organization through a single, unified user interface. For example, members may search for content that originated on a variety of computer systems within the organization. Thus, users can access information from many systems within the organization and can search for content independent of the content's original source. Members may also search through multiple copies of the content, such as the original copy, a first secondary backup copy, and other secondary or auxiliary copies of the content.
Various attributes, characteristics, and identifiers (sometimes referred to as tags or data classifications) can be associated with content. The system may define certain built-in tags, such as a document title, author, last modified date, and so on. Users of the system may also define custom tags, or the system may automatically define custom tags. For example, an administrator may add tags related to groups within an enterprise, such as a tag identifying the department (e.g., finance, engineering, or legal) that created a particular content item. Individual users may also add tags relevant to that user. For example, a user might add a descriptive field, such as a programmer adding a check-in description to identify a change made to a version of a source code document. For content that is inherently unstructured or appears random outside of its intended purpose, tags are an especially effective way of ensuring that a user can later find the content. For example, United States Geological Survey (USGS) data is composed of many numbers in a file that have little significance outside of the context of a map or other associated viewer for the data. Tags allow descriptive attributes or other meaningful information to be associated with the data, for example, so that a searching user can know at a glance that particular USGS data refers to a topological map of a nearby lake. Tags may be associated with offline and online data through a metabase or other suitable data structure that stores metadata and references to the content to which the metadata applies. FIG. 5, discussed below, describes one exemplary data structure used to store user tags associated with content.
The invention will now be described with respect to various embodiments. The following description provides specific details for a thorough understanding of, and enabling description for, these embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures and functions have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments of the invention.
The terminology used in the description presented below is intended to be interpreted in its broadest reasonable manner, even though it is being used in conjunction with a detailed description of certain specific embodiments of the invention. Certain terms may even be emphasized below; however, any terminology intended to be interpreted in any restricted manner will be overtly and specifically defined as such in this Detailed Description section.
Creation of an Offline Copy
As discussed above, the offline content indexing system may create a secondary copy, such as an offline copy, as part of an existing backup schedule performed by an organization. For example, an organization may perform weekly backups that contain a complete copy of the organization's data. It is generally not necessary for the offline content indexing system to consume any further resources of the computer systems within the organization that contain source content, since all of the needed data is typically available in the backup data files. The offline content indexing system may restore the backed up data to an intermediate computer system that is not critical to the operation of the organization, or may operate on the backup data files directly to identify and index content. The offline content indexing system may also create the offline copy using copies of data other than a traditional backup, such as a snapshot, primary copy, secondary copy, auxiliary copy, and so on.
In some embodiments, the offline content indexing system uses a change journal to create an offline copy of content. Modern operating systems often contain built in change journaling functionality that stores a journal entry whenever data is changed within a computer system. The change journal generally contains a step-by-step, sequential, or ordered log of what data changed and how the data changed that can be processed at a later time to recreate the current state of the data. The change journal may be used in conjunction with a full data backup or other data protection mechanisms. The full backup can be used to establish the state of the data at a prior point-in-time, and then the change journal entries can be used to update the state with subsequent changes.
In some embodiments, the offline content indexing system or other system uses a data snapshot to create an offline copy of content. Newer operating systems and several data storage companies offer snapshot software capable of taking a snapshot of the content currently on a computer system with minimal impact to the availability of the system. For example, the snapshot may simply note the current entry in a change journal, and keep track of subsequent change journal entries for updating the snapshot. These snapshots can be transferred from the host system and read on another, less critical system or can be used to replicate the data to a different. The offline content indexing system can then access this intermediate system to identify content and perform content indexing. Other technologies that will be recognized by those skilled in the art, such as disk imaging, mirroring, incremental backups, and so on, may be used in a manner similar to create an offline copy of data for content indexing.
In some embodiments, the offline content indexing system selects an offline copy of data for indexing among several available offline copies. For example, an organization may have several copies of data available on different types of media. The same data may be available on a tape, on a backup server, through network attached storage, or on fast mounted disk media. The offline content indexing system may take into consideration factors such as the access time of a particular media and the scheduled load on a particular offline copy when selecting a copy to use for indexing. For example, an offline copy stored on a hard drive may be preferred over a copy stored on tape due to the faster access time of the hard drive copy and the ability to randomly seek among the data rather than accessing the data sequentially. Alternatively or additionally, a backup server storing or responsible for otherwise desirable data to index scheduled to perform an intensive operation such as encrypting content may be skipped in favor of using a different server responsible for an offline copy that is not expected to be needed by other systems during the time expected to index the content. Similarly, the offline content indexing system may prefer an unencrypted offline copy over an encrypted one due to the extra effort required to decrypt the content to index it.
Indexing of Content
In some embodiments, the offline content indexing system may wait to index content until a request related to the content is received. Searches for offline content may not be as time sensitive as searches for currently available content such that the effort of indexing the content can be postponed until the content is required. For example, in a legal discovery request there may be several days or even weeks available to find content responsive to the request, such that indexing before a request is received would unnecessarily burden an organization's systems.
In some embodiments, the offline content indexing system may postpone content indexing until other storage operations have been performed. For example, one storage operation, called single instancing, may reduce or eliminate redundant files contained in backup data caused by many systems containing the same operating system or application files. By postponing content indexing until after single instancing has occurred, the offline content indexing system does not have to search as much data and may complete the indexing process sooner and with less burden to the organization's systems. A storage policy or other system parameter setting or preference may define how and when content indexing is done, and what other operations are performed before and after content indexing (e.g., indexing content after single instancing). A storage policy is a data structure that stores information about the parameters of a storage operation. For example, the storage policy may define that only some content is to be indexed, or that content indexing should occur late at night when system resources are more readily available.
In some embodiments, the offline content indexing system may update a content index according to an indexing policy. An indexing policy is a data structure that stores information about the parameters of an indexing operation. For example, an organization may create a full backup once a week, and may create an indexing policy that specifies that the index should be updated following each weekly full backup. Indexing the full backup creates a reference copy that the organization can store according to legal requirements (e.g., ten years) to respond to any compliance requests. The indexing policy may also specify that incremental updates are performed on the index based on incremental backups or other incremental data protection operations such as updates from a change journal or snapshot application. For example, incremental backups may be created that only specify the data that has changed since the last full backup, and content changes identified within the incremental backup may be used by the offline content indexing system to update the index to reflect the new state of the content. If the backup data indicates that content has been deleted, the indexed content may be retained, but may be flagged or otherwise identified as having been deleted.
Content Tags
In some embodiments, the offline content indexing system tags or otherwise identifies indexed content with additional information that may help identify the information, for example, in a search for content. For example, indexed content may be tagged with the location of the offline copy in which the information was found, such as a particular backup tape or other offline media. The system may also tag online content, such as tagging a new file with the name of its author. If the content is later deleted, the indexed content may be tagged with the date the content was deleted, the user or process that deleted the content, or the date the content was last available. Deleted content may later be restored, and the indexed content may be identified by a version number to indicate versions of the content that have been available on computing systems throughout the content's history. Other information about the content's availability may also be stored, such as whether the content is stored onsite or is archived offsite, and an estimate of the time required to retrieve the content. For example, if the content is stored offsite with an external archival company, the company may require one week's notice to retrieve the content, whereas if the content is stored on a tape within the organization, the content may be available within an hour. Other factors may also be used to provide a more accurate estimate, such as the size of the content, the offset of the content if it is on tape, and so on. During a search, the search results may indicate whether the time required to retrieve certain content would exceed a retrieval threshold. The system may also prohibit transferring content beyond a given retrieval time to ensure compliance with a policy of the organization.
In some embodiments, the offline content indexing system tags content with classifications. For example, the offline content indexing system may classify content based on the type of application typically used to process the content, such as a word processor for documents or an email client for email. Alternatively or additionally, content may be classified based on the department within the organization that generated the content, such as marketing or engineering, or based on a project that the content is associated with such as a particular case within a law firm. Content may also be classified based on access rules associated with the content. For example, some files may be classified as confidential or as only being accessible to a certain group of people within the organization. The system may identify keywords within the content and classify the content automatically based on identified keywords or other aspects of the content.
Searching
In some embodiments, the offline content indexing system searches for content based on temporal information related to the content. For example, a user may search for content available during a specified time period, such as email received during a particular month. A user may also search specifically for content that is no longer available, such as searching for files deleted from the user's primary computer system. The user may perform a search based on the attributes described above, such as a search based on the time an item was deleted, or based on a project that the item was associated with. A user may also search based on keywords associated with user attributes, such as searching for files that only an executive of the organization would have access to, searching for files accessed by a particular user, or searching for files tagged as confidential.
In some embodiments, the offline content indexing system provides search results that predict the availability of content. For example, content stored offsite may need to be located, shipped, and then loaded back into the organization's systems before it is accessible. The offline content indexing system may provide a time estimate of how soon the content could be available for searching as well as providing limited information about the content immediately based on data stored in the index. For example, the content indexing system may maintain a database of hardware and libraries of media available with the organization, as well as the current location of each of these items such that an estimate can be generated for retrieving the hardware or libraries of media. For example, certain tape libraries may be stored offsite after a specified period of time, and content stored within the tape library may take longer to retrieve than content in a tape library stored onsite in the organization. Similarly, the offline content index system may estimate that data stored on tape will take slightly longer to retrieve than data that is available through magnetic storage over the network.
Figures
Unless described otherwise below, aspects of the invention may be practiced with conventional systems. Thus, the construction and operation of the various blocks shown in FIG. 1 may be of conventional design, and need not be described in further detail herein to make and use the invention, because such blocks will be understood by those skilled in the relevant art. One skilled in the relevant art can readily make any modifications necessary to the blocks in FIG. 1 (or other embodiments or Figures) based on the detailed description provided herein.
FIG. 1 is a block diagram that illustrates components of the system, in one embodiment. The offline content indexing system 100 contains an offline copy component 110, a content indexing component 120, an index searching component 130, an index policy component 140, a data classification component 150, a single instancing component 160, an encryption component 170, and an archive retrieval component 180. The offline copy component 110 creates and identifies offline or other secondary copies of data, such as backup data, snapshots, and change journal entries. The content indexing component 120 creates and updates a content index based on offline copies of data. The index searching component 130 searches the index based on user requests to identify target content. The index policy component 140 specifies a schedule for updating the content index incrementally or refreshing the content index, such as from a full weekly backup. The data classification component 150 adds data classifications to the content index based on various classifications of the data, such as the department that created the data, and access information associated with the data. The single instancing component 160 eliminates redundant instances of information from offline copies of data to reduce the work involved in creating an index of the offline copy of the data. The encryption component 170 encrypts and decrypts data as required to permit access to the data for content indexing. The archive retrieval component 180 retrieves archived content from offsite storage, tape libraries, and other archival locations based on requests to access the content and may also provide estimates of the time required to access a particular content item.
FIG. 1 and the following discussion provide a brief, general description of a suitable computing environment in which the invention can be implemented. Although not required, aspects of the invention are described in the general context of computer-executable instructions, such as routines executed by a general-purpose computer, e.g., a server computer, wireless device or personal computer. Those skilled in the relevant art will appreciate that the invention can be practiced with other communications, data processing, or computer system configurations, including: Internet appliances, hand-held devices (including personal digital assistants (PDAs)), wearable computers, all manner of cellular or mobile phones, multi-processor systems, microprocessor-based or programmable consumer electronics, set-top boxes, network PCs, mini-computers, mainframe computers, and the like. Indeed, the terms "computer," "host," and "host computer" are generally used interchangeably herein, and refer to any of the above devices and systems, as well as any data processor.
Aspects of the invention can be embodied in a special purpose computer or data processor that is specifically programmed, configured, or constructed to perform one or more of the computer-executable instructions explained in detail herein. Aspects of the invention can also be practiced in distributed computing environments where tasks or modules are performed by remote processing devices, which are linked through a communications network, such as a Local Area Network (LAN), Wide Area Network (WAN), Storage Area Network (SAN), Fibre Channel, or the Internet. In a distributed computing environment, program modules may be located in both local and remote memory storage devices.
Aspects of the invention may be stored or distributed on computer-readable media, including magnetically or optically readable computer discs, hard-wired or preprogrammed chips (e.g., EEPROM semiconductor chips), nanotechnology memory, biological memory, or other data storage media. Indeed, computer implemented instructions, data structures, screen displays, and other data under aspects of the invention may be distributed over the Internet or over other networks (including wireless networks), on a propagated signal on a propagation medium (e.g., an electromagnetic wave(s), a sound wave, etc.) over a period of time, or they may be provided on any analog or digital network (packet switched, circuit switched, or other scheme). Those skilled in the relevant art will recognize that portions of the invention reside on a server computer, while corresponding portions reside on a client computer such as a mobile or portable device, and thus, while certain hardware platforms are described herein, aspects of the invention are equally applicable to nodes on a network.
FIG. 2 is a block diagram that illustrates the flow of data through the system 100, in one embodiment. Content is initially stored on a data server 210 that may be a user computer, data warehouse server, or other information store accessible via a network. The data is accessed by a backup manager 220 to perform a regular backup of the data. The backup manager 220 may be contained within the data server 210 or may be a separate component as shown. For example, the backup manager 220 may be part of a server dedicated to managing backup or other storage operations. Backup data is stored in a backup data store 230 such as a network attached storage device, backup server, tape library, or data silo. The content indexing system 240 accesses data from the backup data store 230 to perform the functions described above. As illustrated in the diagram, because the content indexing system 240 works with an offline copy of the data, the original data server 210 is not negatively impacted by the operations of the content indexing system 240.
FIGS. 3-4 are representative flow diagrams that depict processes used in some embodiments. These flow diagrams do not show all functions or exchanges of data, but instead they provide an understanding of commands and data exchanged under the system. Those skilled in the relevant art will recognize that some functions or exchange of commands and data may be repeated, varied, omitted, or supplemented, and other (less important) aspects not shown may be readily implemented.
FIG. 3 is a flow diagram that illustrates the processing of the content indexing component 120 of the system 100, in one embodiment. The component is invoked when new content is available or additional content is ready to be added to the content index. In step 310, the component selects an offline copy of the data to be indexed. For example, the offline copy may be a backup of the data or a data snapshot. In step 320, the component identifies content within the offline copy of the data. For example, the component may identify data files such as word processing documents, spreadsheets, and presentation slides within a backup data file. In step 330, the component updates an index of content to make the content available for searching. The component may parse, process, and store the information. For example, the component may add information such as the location of the content, keywords found within the content, and other supplemental information about the content that may be helpful for locating the content during a search. After step 330, these steps conclude.
FIG. 4 is a flow diagram that illustrates the processing of the index searching component 130 of the system 100, in one embodiment. In step 410, the component receives a search request specifying criteria for finding matching target content. For example, the search request may specify one or more keywords that will be found in matching documents. The search request may also specify boolean operators, regular expressions, and other common search specifications to identify relationships and precedence between terms within the search query. In step 420, the component searches the content index to identify matching content items that are added to a set of search results. For example, the component may identify documents containing specified keywords or other criteria and add these to a list of search results. In step 425, the component generates search results based on the content identified in the content index. In step 430, the component selects the first search result. In decision step 440, if the search result indicates that the identified content is offline, then the component continues at step 450, else the component continues at step 455. For example, the content may be offline because it is on a tape that has been sent to an offsite storage location. In step 450, the component retrieves the archived content. Additionally or alternatively, the component may provide an estimate of the time required to retrieve the archived content and add this information to the selected search result. In decision step 455, if there are more search results, then the component loops to step 430 to get the next search results, else the component continues at step 460. In step 460, the component provides the search results in response to the search query. For example, the user may receive the search results through a web page that lists the search results or the search results may be provided to another component for additional processing through an application programming interface (API). The component may also perform additional processing of the search results before presenting the search results to the user. For example, the component may order the search results, rank them by retrieval time, and so forth. After step 460, these steps conclude.
FIGS. 5 illustrates some of the data structures used by the system. While the term "field" and "record" are used herein, any type of data structure can be employed. For example, relevant data can have preceding headers, or other overhead data preceding (or following) the relevant data. Alternatively, relevant data can avoid the use of any overhead data, such as headers, and simply be recognized by a certain byte or series of bytes within a serial data stream. Any number of data structures and types can be employed herein.
FIG. 5 illustrates a data structure containing entries of the content index, in one embodiment. The offline content indexing system uses this and similar data structures to provide more intelligent content indexing. For example, the offline content indexing system may index multiple copies of data and data available from the multiple copies using a secondary copy of data stored on media with a higher availability based on the location or other attributes indicated by the data structure described below. As another example, the offline content indexing system may prefer an unencrypted copy of the data to an encrypted copy to avoid wasting time unnecessarily decrypting the data. The table 500 contains a location column 510, a keywords column 520, a user tags column 530, an application column 540, and an available column 550. The table 500 contains three sample entries. The first entry 560 specifies a location to a file on the corporate intranet using a web universal resource locator (URL). The entry 560 contains keywords "finance," "profit," and "loss" that identify content within the file. The entry 560 contains tags added by a user that specify that the content comes from the accounting department and is confidential. The entry 560 indicates that a spreadsheet program typically consumes the content, and that the entry is immediately available. Another entry 570 specifies data stored on a local tape that is a personal email, and can be available in about an hour. Another entry 580 specifies an offsite tape that is a presentation related to a cancelled project. The entry 580 refers to offsite data that is available within one week due to the delay of retrieving the archived data from the offsite location.
Conclusion
From the foregoing, it will be appreciated that specific embodiments of the offline content indexing system have been described herein for purposes of illustration, but that various modifications may be made without deviating from the spirit and scope of the invention. For example, web pages are often unavailable and their content may change such that the offline content indexing system could be used to retrieve point in time copies of the content useful for conducting historical analysis. As another example, although files have been described, other types of content such as user settings, application data, emails, and other data objects can all be indexed by the system. Accordingly, the invention is not limited except as by the appended claims.
Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise," "comprising," and the like are to be construed in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to." The word "coupled", as generally used herein, refers to two or more elements that may be either directly connected, or connected by way of one or more intermediate elements. Additionally, the words "herein," "above," "below," and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of this application. Where the context permits, words in the above Detailed Description using the singular or plural number may also include the plural or singular number respectively. The word "or" in reference to a list of two or more items, that word covers all of the following interpretations of the word: any of the items in the list, all of the items in the list, and any combination of the items in the list.
The above detailed description of embodiments of the invention is not intended to be exhaustive or to limit the invention to the precise form disclosed above. While specific embodiments of, and examples for, the invention are described above for illustrative purposes, various equivalent modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. For example, while processes or blocks are presented in a given order, alternative embodiments may perform routines having steps, or employ systems having blocks, in a different order, and some processes or blocks may be deleted, moved, added, subdivided, combined, and/or modified. Each of these processes or blocks may be implemented in a variety of different ways. Also, while processes or blocks are at times shown as being performed in series, these processes or blocks may instead be performed in parallel, or may be performed at different times.
The teachings of the invention provided herein can be applied to other systems, not necessarily the system described above. The elements and acts of the various embodiments described above can be combined to provide further embodiments.
These and other changes can be made to the invention in light of the above Detailed Description. While the above description details certain embodiments of the invention and describes the best mode contemplated, no matter how detailed the above appears in text, the invention can be practiced in many ways. Details of the system may vary considerably in implementation details, while still being encompassed by the invention disclosed herein. As noted above, particular terminology used when describing certain features or aspects of the invention should not be taken to imply that the terminology is being redefined herein to be restricted to any specific characteristics, features, or aspects of the invention with which that terminology is associated. In general, the terms used in the following claims should not be construed to limit the invention to the specific embodiments disclosed in the specification, unless the above Detailed Description section explicitly defines such terms. Accordingly, the actual scope of the invention encompasses not only the disclosed embodiments, but also all equivalent ways of practicing or implementing the invention under the claims.
While certain aspects of the invention are presented below in certain claim forms, the inventors contemplate the various aspects of the invention in any number of claim forms. For example, while only one aspect of the invention is recited as embodied in a computer-readable medium, other aspects may likewise be embodied in a computer-readable medium. Accordingly, the inventors reserve the right to add additional claims after filing the application to pursue such additional claim forms for other aspects of the invention.

This patent is subject to a terminal disclaimer.

Method and system for offline indexing of content and classifying stored data