Locating marker/tracer elements detectable by neutron activated analysis within or on carrier microspheres, including microspheres used in biological experimentation

Abstract

Microspheres are permanently marked with non-radioactive stable isotopes of elements suitably detected by neutron activation analysis. The marked microspheres are suitable to permanently label diverse things. For example, families of stable-multiple-isotope-marked microspheres injected into an animal become lodged by the circulating blood within selected tissues of an animal during blood flow analysis experimentation. Absolute and relative abundances of these stable-isotope-marked microspheres residing within harvested tissues are readily accurately automatically measured in situ within the harvested tissue samples by neutron activation analysis. The quantitatively measured abundance of the isotopes, and associated microspheres, are accurately indicative of the former flow of blood containing the microspheres to the tissue. Microspheres are preferably marked with stable isotopes of gold, antimony, lanthanum, samarium, europium, terbium, holmium, ytterbium, lutetium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, scandium and/or bromide.

What is claimed is:  
     
         1 . A microsphere marked with a non-radioactive stable isotope of an element which isotope and element can be rendered radioactive for detection by neutron activation analysis.  
     
     
         2 . The marked microsphere according to  claim 1   wherein the microsphere physically holds the element;    wherein the marking is by physical association between the element and the microsphere.    
     
     
         3 . The marked microsphere according to  claim 1   wherein the microsphere chemically binds the element;    wherein the marking is by chemical association between the element and the microsphere.    
     
     
         4 . The marked microsphere according to  claim 1  marked with a plurality of non-radioactive stable isotopes.  
     
     
         5 . The marked microsphere according to  claim 1  deployed within a sample wherein the microsphere is marked with an isotope that is so rare within material of the sample that essentially all detection counts during neutron activation analysis can be attributed to presence of the isotope, and essentially none result from the material of the sample.  
     
     
         6 . The marker microsphere according to  claim 1  marked with an isotope that following neutron activation will generate a theoretical specific activity (s) of which exceeds 1×10 10  disintegrations per minute per kilogram of tracer, as appears in the equation for specific activity, s, induced in any parent nuclide during neutron activation: 
         s= 6.02×10 26   φσfA   −1 (0.5) t     1     /t     ½   [1−(0.5) t/t     ½]     
       where: s=specific activity in disintegrations per unit mass (s −1  kg −1 ), σ=flux of neutrons in m −2 s −1 , σ=cross-section for neutron interaction with parent nuclide (m 2 ), f=fractional abundance of the parent nuclide, A=atomic weight of the parent element, t 1 =time between activation and counting (hours), t×activation period (hours), t ½ =half-life of daughter nuclide (hours).  
     
     
         7 . The marked microsphere according to  claim 1  marked with a plurality of isotopes that, following neutron activation analysis, are by their unique energy signatures upon decay from an excited state individually distinguishable from one another.  
     
     
         8 . The marked microsphere according to  claim 1  marked with an isotope that, following neutron activation analysis, produces a daughter nuclide having a half life (t ½ ) greater than one day.  
     
     
         9 . The marked microsphere according to  claim 1  marked with an isotope that, following neutron activation analysis, produces a daughter nuclide having a half life (t ½ ) less than two years.  
     
     
         10 . The marked microsphere according to  claim 1  marked with an isotope that, following neutron activation analysis, produces a daughter nuclide having a half life (t ½ ) of at least two days and shorter than one month.  
     
     
         11 . The marked microsphere according to  claim 1  marked with an element from the group consisting of 
 gold, antimony, lanthanum, samarium, europium, terbium, holmium, ytterbium, lutetium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, scandium and bromide.  
 
     
     
         12 . The marked microsphere according to  claim 1  color coded in accordance with the element with which it is marked.  
     
     
         13 . The marked microsphere according to  claim 1  used in blood flow analysis, the marked microsphere characterized in that it may be detected within a tissue sample resultant from blood flow analysis.  
     
     
         14 . The marked microsphere according to  claim 1  used in high-throughput screening for drug discovery and evaluation, the marked microsphere characterized in that it may be detected within a sample suitable for said high-throughput screening for drug discovery and evaluation.  
     
     
         15 . The marked microsphere according to  claim 1  comprising: 
 a biodegradable microsphere body; with which is associated  
 the non-radioactive stable isotope of an element only during the perpetuation of the physical microsphere body, the isotope he being loosed when the body biodegrades.  
 
     
     
         16 . The marked microsphere according to  claim 15  wherein the biodegradable microsphere body consists essentially of a substance digestible in the gut of a higher animal.  
     
     
         17 . A microsphere marked with a non-radioactive stable isotope of an element the presence of which isotope which can be detected by neutron activation analysis, 
 the isotope following neutron activation generating a theoretical specific activity (s) of which exceeds 1×10 10  disintegrations per minute per kilogram of tracer, as appears in the equation for specific activity, s, induced in any parent nuclide during neutron activation:     s= 6.02×10 26   φσfA   −1 (0.5) t     1     /t     ½   [1−(0.5) t/t     ½]       where: s=specific activity in disintegrations per unit mass (s −1  kg −1 ), φ=flux of neutrons in m −2 s −1 , σ=cross-section for neutron interaction with parent nuclide (m 2 ), f=fractional abundance of the parent nuclide, A=atomic weight of the parent element, t 1 =time between activation and counting (hours), t=activation period (hours), t ½ =half-life of daughter nuclide (hours).    
     
     
         18 . A method of preparing a material for subsequent identification comprising: 
 labeling a material with a microsphere marked with an non-radioactive stable element the presence of which isotope, and element, can be detected by neutron activation analysis;    wherein neutron activation analysis of the marked material or a portion thereof will serve to identify the isotope and element, and thus the marked microsphere, and thus the marked material.    
     
     
         19 . The method according to  claim 18   wherein the marking of the microsphere is by physical association of the material and the microsphere.    
     
     
         20 . The method according to  claim 18   wherein the marking of the microsphere is by chemical association of the material and the microsphere.    
     
     
         21 . The method according to  claim 18   wherein the material labeled is an explosive.    
     
     
         22 . The method according to  claim 18   wherein the material is labeled with a microsphere marked with a non-radioactive stable isotope of an element from the group consisting of    gold, antimony, lanthanum, samarium, europium, terbium, holmium, ytterbium, lutetium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, scandium and bromide.    
     
     
         23 . A material labeled by the method according to  claim 18 .  
     
     
         24 . A method of measuring blood flow to tissue by use of microspheres collectively marked with a non-radioactive stable isotope that may be induced to emission by stimulation with a neutron flux, the method comprising: 
 introducing a great multiplicity of non-radioactive stable-isotope-marked microspheres within the circulating blood of an animal;    harvesting a tissue sample of the animal which, due to previous retention of microspheres from the circulating blood, contains a multiplicity of marked microspheres therein;    subjecting the harvested tissue containing the multiplicity of microspheres to a source of neutron flux in a process of neutron activation analysis so as to thereby induce effectively all, each and every one, of the stable isotopes within the multiplicity of marked microspheres to assume an elevated energy state from which each isotope will eventually decay;    counting decays per unit time of stable isotopes from their elevated states as an indication of the presence of the stable isotopes, and thus of the marked microspheres containing the isotopes, the abundance of isotopes and marked microspheres serving as an indication of the proportion of the multiplicity of marked microspheres that were within the harvested tissue sample relative to the great multiplicity of marked microspheres that were introduced into the circulating blood of the animal; 
 wherein the indicated proportion is also an indication of the blood flow of the animal to the tissue at the time of the introducing, and before the time of the harvesting.  
   
     
     
         25 . The method of measuring blood flow to tissue according to  claim 24   wherein the marked microspheres are of different types each containing isotopes that may be individually distinguished from other isotope types during neutron activation analysis; and    wherein the detecting and measuring of the magnitude of the isotope decays is an indication of not only the proportion, but also the absolute number, of the multiplicity of marked microspheres that were within the harvested tissue sample relative to the number of the great multiplicity of marked microspheres that were introduced into the circulating blood of the animal.    
     
     
         26 . A method of (i) labeling samples coupled with (ii) a subsequent identification by process of neutron activation analysis of at least one of the samples so labeled, the sample labeling and identifying method comprising: 
 uniquely marking each of a plurality of types of microspheres with at least an associated one of a plurality of non-radiative stable isotopes each of an element the presence of which can be detected by neutron activation analysis;    uniquely labeling each of a multiplicity of samples with at least an associated one type of a plurality of types of microspheres;    irradiating an entire sample of unknown identity, which sample is uniquely labeled with at least an associated one type of the plurality of types of microspheres, with radiation sufficient to excite all the stable isotopes of all the types of microspheres to an associated higher energy state; and    detecting decay events of the at least one excited stable isotope within the irradiated sample so as to uniquely identify the microsphere type with the sable isotope is associated, and from this identified microsphere type, the uniquely associated sample; 
 wherein a signature of radioactive decay by each stable isotope from its associated excited state is uniquely detectable from among decays of all other isotopes from their excited states;  
 wherein, because (i) the signature of each stable isotope is uniquely detectable and (ii) each type of microsphere is uniquely marked with at least one stable isotope, so also is each type of the plurality of types of microspheres uniquely detectable from among all other types of microspheres;  
 wherein, because (i) each type of the plurality of types of microspheres is uniquely detectable from among all other types of microspheres, and (ii) each sample is uniquely labeled with at least an associated one of a plurality of types of microspheres, so also is each sample uniquely detectable from among all others of the multiplicity of samples.  
   
     
     
         27 . The sample labeling and identifying method according to  claim 26   wherein the unique marking of each of a plurality of types of microspheres is with a predetermined quantity of the least an associated one of a plurality of non-radiative stable isotopes;    wherein the unique labeling of each of a multiplicity of samples is with a predetermined quantity of at least an associated one type of a plurality of types of microspheres; and wherein the detecting of the decay events of the at least one excited stable isotope within the irradiated sample so as to uniquely identify the microsphere type with the stable isotope is associated further comprises: 
 detecting the rate of the decay events as an indication of the abundance of the isotopes, which is in turn indicative of the abundance of the microspheres, within the sample.