Patent Application
20210206957
The present invention belongs to the field of material contamination or degradation detection, particularly to the use of isotopically labelled materials for the detection of material contamination in industrial processes, space research or in biomedical applications.
The space exploration and the search of life in other celestial bodies has suffered an exponential increase in the last 60 years. Technological advances have made it possible to set objectives and achieve goals that were unthinkable before 1957, the date on which the first successful satellite, Sputnik 1, was launched. This event launched the space race, and with it, a large number of missions that have explored planets, satellites and comets from our galaxy.
The beginning of these contacts brought with it concern about the possible contamination produced in the visited bodies (Forward contamination), and that received in the return missions (Backward contamination). To study how to minimize the effect of these processes and issue recommendations the COSPAR (Committee on space research) was formed in 1964. Its resolutions were ratified by the United Nations in the “External Space Treaty” of 1967. Space agencies have adopted these recommendations in their procedures and the Planetary Protection protocols are strictly followed in all space missions. The cleaning procedures and the control systems for biological, molecular and particle contamination are very rigorous and are present in all phases of the mission: design, manufacture, assembly, integration, testing, storage, transportation, preparation for launch, launch and orbit.
Especially sensitive to cross contamination are the scientific missions in situ whose objective is the search for life precursors. The analytical equipment shipped aboard the rovers and probes are increasingly sensitive and the detection range is becoming smaller (ppb). A natural pollution, or accidental, produced by the material transported from the Earth in a mission can produce a false positive in the search for life precursors, where biological traces as simple as C—H, C—O or C—N links are looked for.
Advances in polymer technology have allowed to improve the mechanical and thermal properties, which together with its lightness, has made polymers very interesting candidates for spatial use as structural materials. As functional materials its use is even more widespread: wiring, adhesives, plastic connectors, lubricants or gaskets that are present in any mission.
However, the simple signals of the mentioned links could be detected in a large number of the polymers, which are the fundamental basis of their composition, and in case of contamination, produce a false positive in the analysis of the samples.
US2010063208 A1 and US2010062251 A1 relate to taggant fibers which can be manufactured using polymeric materials. US2015377841 A1 disclose fibers which contain identification fibers, which are chemically marked or tagged. None of these documents disclose any material marked isotopically. Also, in these three documents, the marked fibers are used specifically for tagging the material. However, the present invention relates to materials which do not incorporate any component specifically and only for marking or tagging the material.
The present invention provides a material which allows the detection of any contamination or degradation or wear of said material in a simple and very reliable way. The inventors of the present invention have found that an isotopically marked functional material can be traced and, moreover, that its different components can be traced so as to identify if there has been any contamination or degradation of the material in general or of any of its components in particular.
In a first aspect, the present invention relates to a material comprising a synthetic functional polymer and optionally at least one functional additive, wherein said material is marked with at least one isotope of table 1, wherein the isotope or isotopes are present in a functional component of the material. Said functional component or components of the material where the isotope or isotopes are present is not used in the material for marking said material but has another function in said material other than marking the material, such as a structural function, or a function such as that of a plasticizer, a flame retardant, a filler, an antioxidant, a metal scavenger, a UV protector, a photostabilizer, a heat stabilizer, an impact modifier, etc. Thus, the marked functional component is not present in the material only for the purpose of labelling or tagging the material.
In a preferred embodiment of the first aspect, the present invention relates to a material comprising at least one synthetic functional polymer and optionally at least one functional additive, wherein said material is marked with at least one isotope of table 1, wherein the isotope or isotopes are present in a functional component of the material.
In a preferred embodiment of the first aspect, the material comprises more than one component and the same isotope is used for marking different components.
1H
36Ar
68Zn
97Mo
123Sn
150Sm
178Hf
2H
38Ar
70Zn
98Mo
120Te
152Sm
179Hf
3He
40Ar
69Ga
96Ru
122Te
154Sm
180Hf
4He
39K
71Ga
98Ru
123Te
153Eu
181Ta
6Li
41K
70Ge
99Ru
124Te
154Gd
182W
7Li
40Ca
72Ge
100Ru
125Te
155Gd
183W
9Be
42Ca
73Ge
101Ru
126Te
156Gd
184W
10B
43Ca
74Ge
102Ru
127I
157Gd
186W
11B
44Ca
75As
104Ru
124Xe
158Gd
185Re
12C
46Ca
74Se
103Rh
126Xe
160Gd
184Os
13C
45Sc
76Se
102Pd
128Xe
159Tb
187Os
14C
46Ti
77Se
104Pd
129Xe
156Dy
188Os
14N
47Ti
78Se
105Pd
130Xe
158Dy
189Os
15N
48Ti
80Se
106Pd
131Xe
160Dy
190Os
16O
49Ti
79Br
108Pd
132Xe
161Dy
192Os
17O
50Ti
81Br
110Pd
134Xe
162Dy
191Ir
18O
51V
80Kr
107Ag
133Cs
163Dy
193Ir
19F
50Cr
82Kr
109Ag
132Ba
164Dy
192Pt
20Ne
52Cr
83Kr
106Cd
134Ba
165Ho
194Pt
21Ne
53Cr
84Kr
108Cd
135Ba
162Er
195Pt
22Ne
54Cr
86Kr
110Cd
136Ba
164Er
196Pt
23Na
55Mn
85Rb
111Cd
137Ba
166Er
198Pt
24Mg
54Fe
84Sr
112Cd
138Ba
167Er
197Au
25Mg
56Fe
86Sr
114Cd
139La
168Er
196Hg
26Mg
57Fe
87Sr
113In
136Ce
170Er
198Hg
27Al
58Fe
88Sr
112Sn
138Ce
169Tm
199Hg
28Si
59Co
89Y
114Sn
140Ce
168Yb
200Hg
29Si
58Ni
90Zr
115Sn
142Ce
170Yb
201Hg
30Si
60Ni
91Zr
116Sn
141Pr
171Yb
202Hg
31P
61Ni
92Zr
117Sn
142Nd
172Yb
204Hg
32S
62Ni
94Zr
118Sn
143Nd
173Yb
203Tl
33S
64Ni
93Nb
119Sn
145Nd
174Yb
205Tl
34S
63Cu
92Mo
120Sn
146Nd
176Yb
204Pb
36S
65Cu
94Mo
122Sn
148Nd
175Lu
206Pb
35Cl
64Zn
95Mo
124Sn
144Sm
176Hf
207Pb
36Cl
66Zn
96Mo
121Sb
149Sm
177Hf
208Pb
37Cl
67Zn
In another preferred embodiment of the first aspect, the material comprises more than one component and wherein a different isotope is used for marking different components.
In a preferred embodiment of the first aspect, the isotope is introduced in a specific position in a monomer of the synthetic polymer.
In a preferred embodiment of the first aspect, the at least one isotope is selected from 2H, 13C, 15N, 17O, 18O, 29Si, 30Si, 33S, 34S, 36S, 37Cl. These isotopes form covalent bonds in organic compounds.
The term “functional” as used herein means that the synthetic polymer or the additive's purpose or function is not exclusively marking the material, that is, the synthetic polymer or additive has a function other than marking the material. For example, the function of the synthetic polymer may be structural. For example, the function of the additive may be a plasticizer, a flame retardant, a filler, an antioxidant, a metal scavenger, a uv protector, a photostabilizer, a heat stabilizer, or an impact modifier. The term “functional” as used herein should not be understood as “functional group” but as explained above.
The expression “present in a functional component of the material” also means that the component of the material which is isotopically marked has a function other than marking the material. For example, when the component that is isotopically marked is the synthetic polymer, this polymer may be a structural component, useful for its mechanical properties, or a functional component, useful for its chemical, magnetic, electronic properties, etc., and this polymer will be useful for other reasons than for being marked.
The term “component” as used herein means any constituting part of a larger whole, any constituent. In the present description, the term “component” refers to the material and, therefore, refers to any constituting part of the material.
The term “marked” or “marking” as used herein means that the material in general and the marked component in particular, comprise a different isotopic ratio than the isotopic ratio present in the medium or environment where the material is used. For example, for space material to be used in Mars, the isotopic environment in the material will be different than the isotopic environment in Mars. For space material to be used in the Moon, the isotopic environment in the material will be different than the isotopic environment in the Moon. For a prosthetic material to be used in the human body, the isotopic environment in the material will be different than the isotopic environment in the human body. The skilled person is fully aware of how to prepare the materials of the present invention, once the particular isotopic environment for the material has been chosen (see for example Nikonowicz, E. P. et al. 1992 Nucleic acids research, 20 (17), 4507-4513; Schmidt, O., and Scrimgeour, C. M. (2001). Plant and Soil, 229(2), 197-202; Liu, L., and Fan, S. (2001) Journal of the American Chemical Society, 123(46), 11502-11503; Mulder, F. M. et al. 1998 Journal of the American Chemical Society, 120(49), 12891-12894; U.S. Pat. No. 6,541,671; Park, S. et al (2012). Nature communications, 3, 638; Connolly, B. A., and Eckstein, F. (1984). Biochemistry, 23(23), 5523-5527; Crosby, S. R., et al. (2002). Organic letters, 4(20), 3407-3410; Yao, X. et al. (2003) Journal of proteome research, 2(2), 147-152).
The terms “labelled” and “marked” are used interchangeably in the present description.
The expression “isotopic environment” as used herein refers to the percentage of each isotope of each chemical element in a certain physical environment, i.e. in a certain planet, satellite, etc. The expression “different isotopic environment” as used herein means that upon detecting the percent of a certain isotope of a certain chemical element in the material and in a particular natural environment, different percentages will be obtained. For example, for a material marked with 2H (deuterium) to be used in Mars, its minimum mark will be 5 times the abundance of 2H in Mars, which is 0.3895% of the Hydrogen atoms in the marked component of the material will be 2H.
For example, the plasticizer dioctyl phthalate (DOP) can be added in a 0.1 weight % to the composition of a material comprising a synthetic polymer. If DOP is marked at the 50% of a set atomic position, this means that this component of the material is marked and if it degasifies, the degraded component will be detected because of the different signals generated by this 50% of marked positions.
The present invention allows to have different marking in each component which allows to identify the component which is suffering degradation.
A material can be 100% traceable if all of its components are marked and each one is marked using a specific marking, which can be associated to a specific component or material upon detection.
In a preferred embodiment of the first aspect, the said material is an industrial material or a space material or a prosthetic material.
In a preferred embodiment, the material is not a material susceptible of being falsified such as documents such as land titles, currency, or identification documents such as passports, etc.
The expression “industrial material” as used herein refers to any material suitable for industrial applications. Materials suitable for industrial applications must be validated according to the characteristics of the specific field of use. Two examples of industrial material are:
The expression “space material” as used herein refers to any material suitable for a space mission. Materials suitable for space missions must be validated according to the requirements of each mission in terms of space environment effects, such as vacuum, heat, thermal cycling, radiation, debris, etc. and in terms of induced space environment effects, such as contamination, secondary radiations and spacecraft charging. These space environment effects are defined by the external physical world for each mission: atmosphere, meteoroids, energetic particle radiation, etc. The induced space environment is that set of environmental conditions created or modified by the presence or operation of the item and its mission. The space environment also contains elements which are induced by the execution of other space activities (e.g. debris and contamination).
The expression “prosthetic material” as used herein refers to any material suitable for a use in a prosthesis, preferably in the animal body, more preferably in the human body. The prosthesis may be external or internal to the body. Materials suitable for being used in a prosthesis are biocompatible and do not cause adverse local or systemic effects. The biocompatibility of the prosthetic material is tested according to ISO 10993. Also, USP Class VI standard may be used to determine the biocompatibility of the material. Preferably, ISO 10993 is used to test the biocompatibility.
In a preferred embodiment of the first aspect, at least 0.3% of the atoms of the chemical element of the isotope are marked, in respect of the total number of atoms of that chemical element in the marked component of the material. Preferably, at least 0.5% of the atoms of the chemical element of the isotope are marked, in respect of the total number of atoms of that chemical element in the marked component of the material. More preferably, at least 1% of the atoms of the chemical element of the isotope are marked, in respect of the total number of atoms of that chemical element in the marked component of the material. In a more preferred embodiment, at least 2% of the atoms of the chemical element of the isotope are marked, in respect of the total number of atoms of that chemical element in the marked component of the material. In an even more preferred embodiment, at least 5% of the atoms of the chemical element of the isotope are marked, in respect of the total number of atoms of that chemical element in the marked component of the material. In another embodiment, at least 30% of the atoms of the chemical element of the isotope are marked, in respect of the total number of atoms of that chemical element in the marked component of the material. The minimum marking of the material will depend on the technique intended to be used for detection and its sensitivity.
In a preferred embodiment of the first aspect, the isotopic mark is detected by FTIR, Raman, GC/MS, RMN-H, RMN-C, UV-visible spectroscopy. The isotopic mark is detected by any analytical technique that can detect the differences between the natural isotopic environment and the induced isotopic environment in the material. Preferably, the isotopic mark is detected by FTIR, Raman, GC/MS, RMN-H, RMN-C and/or UV-visible spectroscopy. More preferably, the isotopic mark is detected by Raman or GC/MS.
The materials of the present invention are characterized physico-chemically analysing their TGA, DSC, degree of crystallinity, glass transition temperature, gel permeation chromatography (GPC), FTIR, Raman and H-NMR. The degradation/contamination/wear of the materials of the present invention can be detected by means of the same analytical techniques used in the rover of the Exomars 2020 mission: Raman, GC/MS, etc. For example, the analytical techniques used in Martian rovers to search organic life signatures are gas chromatography with mass spectroscopy (GC/MS), laser desorption with mass spectroscopy (LD/MS) and Raman spectroscopy.
For those materials to be used in space, said materials will undergo the relevant spatial validation tests, required for all materials that participate in space missions, and which are determined by the type of mission, the function of the component, and its exposure to environmental agents.
For the materials described in the present invention, the rules of the ESA (European Space Agency) have been followed, and the validation tests have been those determined by the following standards:
For using the material of the invention as a prosthetic material, the detection of the material degradation by LC/MS technique offers high sensitivity, area selectivity and the ability to discriminate between release products originating from the prosthetic material and those naturally present in biological fluids. In the manufacturing of the prosthetic material there are following main steps: compounding, solution mixing, powder mixture and sintering. The material can be fully labelled or only labelled in layers, for example, multilayer coating could be used with labelled layers as degradation witness. In a particular embodiment, the prosthetic material has at least one witness layer where the structural polymer is marked. In another embodiment, the prosthetic material has at least one witness layer where a functional additive is marked. The amount of marked atoms (ratio of isotopic labelling) will depend on the strategy used (full marking/labelling or multilayer marking/labelling) and the sensitivity of the detection method used. The manufacturing and labelling technique is adapted and depends on the thermal properties of the synthetic polymer or polymers in the material. For example, for fluorinated polymers it is preferred to use a mixing powder and further sintering. The temperature profile of the process varies from 60-450° C. and the pressure, from 1 bar to 1,500 bar. For using the material of the invention as a prosthetic material, said materials must match the usual standards for this kind of devices and must fulfil the requirements of the validation tests established for each particular case.
An advantage of the present invention is the early and non-invasive detection of the degradation of an implant or a medical device, for example simply analysing a blood sample.
In a preferred embodiment of the first aspect, the synthetic polymer is an addition polymer or a condensation polymer. Preferably, the synthetic polymer is a polyolefin, a polyester, a polyurethane, a polyimide, a polyacrylate, a polysiloxane, a polyepoxide, a fluorinated polymer or a combination thereof. more preferably, the synthetic polymer is polyethylene (PE), polyethylene terephthalate (PET), polyamide (PA), ethylene tetrafluoroethylene (ETFE), polytetrafluoroethylene (PTFE), perfluoroalkoxy alkane (PFA), polyetheretherketone (PEEK), polyethersulphone (PES), polysulfone, polyetherimide (PEI) or a copolymer o terpolymer thereof.
Examples of synthetic bioabsorbable polymers that may be used for prosthetic materials are polyglycolide, or polyglycolic acid (PGA), polylactide, or polylactic acid (PLA), poly ε-caprolactone, polydioxanone, polylactide-co-glycolide, e.g., block or random copolymers of PGA and PLA, and other commercial bioabsorbable medical polymers. Preferred is spongy collagen or cellulose.
In a preferred embodiment of the first aspect, the material is a plastic, an adhesive, a coating, a varnish, a tape, a film, a paint, an ink, a lubricant, a potting, a sealant, a foam, a rubber, a wire or a cable.
In a preferred embodiment of the first aspect, the material is an artificial heart, artificial heart valve, implantable cardioverter-defibrillator, cardiac pacemaker, coronary stent, an artificial bone, an artificial joints, pin, rod, screw, plate, a biodegradable medical implants, a contraceptive implant, a breast implant, a nose prosthesis, an ocular prosthesis or an injectable filler.
In a second aspect, the present invention relates to the use of the material of the first aspect in the detection of material contamination or degradation or wear. For example, for space material, the present invention relates to the use of said material for the detection of any material contamination. For prosthetic material, the present invention relates to the use of said material for the detection of its degradation. For industrial materials, the present invention relates to the use of said material for the detection of the material wear.
In a third aspect, the present invention relates to the use of the material of the first aspect for marking a composite material. Preferred composite materials comprise at least one of carbon fibre, polyethylene, polypropylene, nylon or kevlar. Preferably, the composite material comprises a binder and reinforcement fibres and/or particles. Said binder and/or reinforcement fibres and/or particles could be also polymeric.
In a preferred embodiment of the first aspect of the present invention, the material comprises different components and all the marked components are marked with the same isotope.
In another aspect, the present invention relates to the use of a non polymeric compound suitable for being a functional component of a material of the first aspect and which is marked with at least one isotope of table 1, for detecting contamination, degradation or wear of a material.
In order to provide a better understanding of the invention, the following is a detailed explanation of some of the preferred embodiments of the invention, which is provided to give an illustrative example of the invention but which, by no means, should be considered to limit the same.
As an example of isotopically labelled structural or functional material for the application of space contamination detection, PET polymers (Polyethylene terephthalate) have been synthesized and have the same technical characteristics as the PET used as the calibrator of the Raman spectrometer that will go aboard the Exomars. These polymers have been synthesized starting from:
The synthesis has been carried out by additive polymerization (polycondensation in interface), in a two-phase system composed of an organic and an inorganic phase, with the following conditions:
The monomers were added in a staggered manner in two independent phases. The interfacial polymerization proceeded then in the following way:
The ratio of isotopically labelled polymer was graduated by employing different mixtures of the monomers and their deuterated analogues. For the example, 5 different compositions were made:
Purification:
The purification of the resulting material was carried out in the following manner:
After this purification, it was necessary to carry out a bakeout to release the non-crosslinked monomers, and the residues of additives and solvent, typical in materials for space use.
Over a solution of 0.001 to 17 kg of NaOH (0.30 mol/L) in water, 0.0035 to 500 mol of a mixture of ethyleneglycol and ethylene-d4 glycol (ratio from 0 to 100%; total concentration 0.41 mol/L) was added under stirring at a moderate speed. Subsequently, 0.01 mol-% of phase transfer catalyst (for example, tetrabutylammonium bromide) dissolved in 0.001 to 10 liters of water were added. A mixture of terephthaloyl chloride and terephthaloyl-d4 chloride (ratio from 0 to 100%; molar ratio diol/diacid chloride 1:1) was dissolved in chloroform (ratio water/chloroform 70:30). The organic phase was then added over the aqueous layer under vigorous stirring and mixing continued for 5 to 60 minutes. Acetone was added to the reaction vessel and the polymer was filtered off and washed with acetone to remove unreacted monomers. The material was subsequently washed three times with water and then filtered off. The final product was dried to constant weight in a vacuum oven at 40° C.
Ethylene and ethylene-d4 were introduced at different ratios and at a moderate flow to a stirred solution containing a 1 to 1 mixture of TiCl4 and AlEt3 in hexanes under N2 atmosphere. When the reaction mixture became thick, the mixture was hydrolyzed by addition of several amounts of ethanol. The resulting material was subsequently washed several times with ethanol, filtered and dried.
The PET polymer was marked using deuterium in the 100% of the hydrogen atomic positions of both precursor monomers (ethylenglycol-d4, and terephthaloyl chloride-d4).
In order to detect/identify the marked PET, different techniques were used:
Raman Spectroscopy
Raman spectroscopy is a non-destructive technique that does not need the previous preparation of the sample.
For this study the Raman spectrometer used was a RAMAN Horiba XPlora with Laser: 532 nm (Green) and Confocal microscope 10×.
We found that the isotopic substitution of deuterium (2H) instead of protium (1H) in the 100% of hydrogen positions (aliphatic and aromatic) in PET caused little differences in many of the detected signals, but in those in which the hydrogen interaction was higher, the shift of the signals was more notorious and easy to differentiate in the marked sample. Some examples of the most representative were the following:
Only the deuterated signals (Table 2) appeared in the spectrum, clearly differentiated from the analogous protium examples that did not appear in that case. The ratio of the intensity of equivalent signals must be proportional to the ratio of the marked:non-marked positions.
In the case of 50% of marked positions in both precursor monomers, the protium and deuterium signals will appear in the spectrum with same intensity, but keeping the shift that allows to differentiate.
Gas Chromatography and Mass Spectrometry (GC/MS)
50 mg of the powdered 100% marked PET was dissolved in 1 ml of acetone for HPLC (≥99.9%).
The GC/MS system used was a Varian Saturn 2200. The parameters of the method were:
1 μl of the PET/acetone solution was injected directly in the 1177 injector of the GC, using a 5 μl Hamilton syringe.
As it happened in the Raman study, only the mass of the deuterated fragments (table 3) appeared in the chromatogram.
The +1 (M/z) caused by every deuterium introduced instead of a protium has an accumulative effect, and in the PET case, the 8 marked position generates a +8 (M/z) for the molecular ion, and at least +4 (M/z) in the most of identification fragments:
In the case of 50% of marked positions in both precursor monomers, the protium and deuterium signals appear in the chromatogram with same intensity. Since the isotopic differences do not affect significantly the interaction of compounds with the chromatographic column, the separation was not possible (even for longer and soft methods) and the retention time was almost the same.
To solve this, the GC/MS systems allows the selective plot of the preferred masses. Protium and deuterium signals (table 3) could be plotted separately and compare the number of accumulated counts of every species.
The ratio of the intensity of the accumulated counts of the masses detected must be proportional to the ratio of the marked:non-marked positions.
Three additives of common polymeric use are presented as examples of identification by GC/MS. The methodology of study and identification will be the same as for PET:
Dioctyl Phthalate (DOP)
DOP is used as plasticizer.
Gas Chromatography and Mass Spectrometry (GC/MS)
The +1 (M/z) caused by every deuterium introduced instead of a protium has an accumulative effect, and in the Dioctyl-Phthalate-d38 (DOP) case, the 38 marked positions generates a +38 (M/z) for the molecular ion, and at least +4 (M/z) in the most of identification fragments:
Decamethyltetrasiloxane
Decamethyltetrasiloxane is used as adsitive in adhesives and lubricants.
Gas Chromatography and Mass Spectrometry (GC/MS)
The +1 (M/z) caused by every deuterium introduced instead of a protium has an accumulative effect, and in the decamethyltetrasiloxane-d30 case, the 30 marked positions generates a +30 (M/z) for the molecular ion, and at least +9 (M/z) in the most of identification fragments:
Benzotriazole
Benzotriazole is used as UV photostabilizer.
Gas Chromatography and Mass Spectrometry (GC/MS)
The +1 (M/z) caused by every deuterium introduced instead of a protium has an accumulative effect, and in the Benzotriazole-d4 case, the 4 marked positions generates a +4 (M/z) for the molecular ion, and at least +3 (M/z) in the most of identification fragments:
| Number | Date | Country | Kind |
|---|---|---|---|
| EP18382468 | Jun 2018 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/066777 | 6/25/2019 | WO | 00 |
