Standards for EHS Research Workshop, NIST, Sept. 12-12, 2007 Development and Production of Reference...

Standards for EHS Research Workshop, NIST, Sept. 12-12, 2007

Development and Production of Reference Materials

Debra L. KaiserChief, Ceramics Division

Materials Science and Engineering Laboratory


Material-Based Standards: Definitions

International Vocabulary of Metrology* (IVM):

• Reference Material

• Certified Reference Material (CRM)

NIST:

• Standard Reference Material (SRM)

• Reference Material (RM)

*published by the International Organization for Standards (ISO) http://www.iso.org/iso/publications_and_e-products/


Reference Material: IVM Definition

Material or substance whose property values are sufficiently homogeneous and well established to be used for:

• Calibrating an apparatus

• Assessing a measurement method

• Assigning values to materials

• Quality control

Properties may be:

• Quantitative, e.g., amount or size of substance or species

• Qualitative, e.g., identity of substances or species


Certified Reference Material: IVM Definition

All from the previous slide for a Reference Material plus:

• Accompanied by a certificate

• Property values are certified as traceable to an accurate realization of the unit in which the property values are expressed

nanoparticle diameter traceable to a known wavelength of light via a step height transfer artifact

• Each certified value is accompanied by an uncertainty at a stated level of confidence


NIST Standard Reference Material (SRM)

All from the previous slide for a CRM plus:

• Meets NIST-specific certification criteria*

• Issued with a Certificate of Analysis that details its characterizations and provides information regarding its appropriate uses

• Certified values are usually measured by two or more independent methods at NIST

• Certified values and uncertainties for which NIST has the highest confidence because it has fully investigated or accounted for all known or suspected sources of bias

*NIST Special Publication 260-136


NIST Reference Material (RM)

All from the previous slide for a CRM plus:

• Issued with a Report of Investigation that details its characterizations and provides information regarding its appropriate uses

• Reference (not certified) values that are the best estimates of the true values

• Associated uncertainties may reflect only measurement precision and may not include all sources of uncertainty

• Reference values may be measured by only one method at NIST


Stages of NIST RM Development

Development

• Underpinning measurement science and technology

• Customer needs and market assessments indicate an RM is required to address barriers to innovation

• Select material and source, define reference and information values, select measurement methods, establish testing plan

• Develop a prototype whose reference values are traceable

Production

Research

• Heterogeneity testing, generate reference and information values, perform statistical analyses

• Generate Report of Investigation and release RM

Development and production stages typically take 1-3 years


RM Report of Investigation

Reference valueA value best estimate of the true value provided on the NIST report of investigation, where all known or suspected sources of bias have not been fully investigated by NIST.

Information valueA value that will be of interest and use to the RM user, but insufficient information is available to assess the uncertainty associated with the value or a limited number of analyses were performed. Measurement variance may be reported.


Material Considerations for RM

• Source material

• Commercially available “off-the-shelf” material

• “Custom-made” by NIST or an external party

• Sufficiently large, homogeneous quantity of material to produce specified number of units (“feedstock”)

• Stability of RM

• Ideally stable for many years; may not be possible for some materials

• Periodic assessment of stability


Current NIST Nanoparticle SRMs and RMs

• Polystyrene spheres

• SRM 1963a: nominal 100 nm diameter

• SRM 1964: nominal 60 nm diameter

• Uses: calibration and validation of particle sizing instruments

• Gold nanoparticles

• RM 8011, 8012, and 8013

• Nominal 10 nm, 30 nm, and 60 nm diameter citrate-stabilized colloidal gold

• In production

• Available for sales by December 2007

TEM image of SRM 1963a

AFM image of 30 nm gold


Gold Nanoparticle RMs

• NCI requested that NIST provide gold nanoparticle RMs (January 2006)

• NCI-NCL (Nanotechnology Characterization Laboratory) and NIST jointly defined the scope of the first-generation of RMs (June 2006)

• Customers & uses

• Material type – unconjugated colloidal gold

• Nominal particle diameters

• Size of RM unit, number of RM units

• Reference and information values

• NIST development stage started in July 2006; involved eight Divisions in five NIST Laboratories

• NIST production stage started in February 2007

• NCI provided the majority of the funding for material and labor costs for the RM development and production

TEM image of 60 nm gold


Intended Uses of RMs 8011, 8012, 8013

• Evaluate and qualify methodology and instrument performance related to the physical and dimensional characterization of nanoscale particles used in pre-clinical biomedical research

• Development and evaluation of in vitro assays designed to assess the biological response (e.g., cytotoxicity, haemolysis) of nanomaterials

• Use in interlaboratory comparisons

Widely recognized that the RMs will have value beyond the biomedical research community—early interest from NTP, EPA, NIOSH


RM Material and Packaging

Citrate-reduced gold in aqueous solution (0.01% HAuCl4)

Produced by BBI to NIST specifications in 8 liter batches for 3 nominal sizes:

RM8011 – 10 nm

RM8012 – 30 nm

RM8013 – 60 nm

Gold solutions homogenized, hermetically sealed in 5 mL glass ampoules under argon, gamma-irradiated to insure sterility.

Each RM “package” will contain 2 x 5 mL ampoules Long term stability (“shelf-life”) will be monitored by DLS/UV-Vis

OH

HO

O

OH

O

O

HO

H2O, 100OCHAuCl4

Cit-

Cit-

Cit-

Cit-

G Frens, Nature Physical Science 20 241 (1973)


Reference Values

Technique Form Preparation

AFM1 deposited onto Au(111) - mica substrate

centrifugation to remove citrate salt, then drying

SEM2 deposited on SiO2 grid aminosilane-modified SiO2 coated grid used for electrostatic deposition

TEM3 deposited on SiO2 grid aminosilane-modified SiO2 coated grid used for electrostatic deposition

DLS4 in solution, diluted & native filtered to remove large “dust” particles

DMA aerosol centrifugation to remove citrate salt, addition of electrolyte (NH4OAc) then electrospray

SAXS in solution, undiluted enclosed in liquid cells

Dimensional reference values: mean particle diameter in solution, as an aerosol, and deposited on a substrate

AFM: atomic force microscopy; SEM: scanning electron microscopy; TEM: transmission EMDLS: dynamic light scattering; DMA: differential mobility analysis; SAXS: small-angle x-ray scattering

1Traceable to a known wavelength of light via a 68.9 nm silicon step height transfer artifact2Traceable to a calibrated AFM using a lattice transfer artifact3Instrument calibrated using negatively stained catalase crystals4Instrument calibrated using NIST SRM 1964, nominal 60 nm polystyrene spheres


Informational Values

ICP-OES: inductively-coupled plasma optical emission spectrometry

• Electro-chemical properties:

• Au concentration by ICP-OES

• Citrate and chloride ion concentrations by ion chromotography

• pH by electrochemical methods

• Electrolytic conductivity by conductometric methods

• Zeta potential by electrophoretic light scattering

• Optical absorption by UV-Vis spectroscopy

• Chromatographic separation trace by asymmetric-flow field flow fractionation

• Sterility assessment


Report of Investigation - Content


Report of Investigation - Content

Introductory/Summary Statement Reference Value Statement

Reference Value Table (assigned value + uncertainty)

Expiration of Material Maintenance of RM Value Assignment (stability evaluation)

Contribution Acknowledgements (participants, funding)

Handling and Storage Instructions for Use & Cautions to User Material Source and Processing Heterogeneity Assessment Value Assignment and Uncertainty Analysis Information Value Statement

Informational Values/Data (footnoted methods) Methodology for Reference Value Measurements

(instrument, sample preparation procedures, measurement procedures)

References


Post RM Production Activities & Goals

Maintenance of RM Value Assignment

Assessment of long-term stability/shelf-life

DLS, UV-Vis will be used to periodically monitor RM for substantive changes that affect the reference value assignment

Substantive changes will be addressed and further testing conducted as necessary.

Purchasers can be notified of the change.

Peer Reviewed Publication

Science-based analysis of size measurements with the goal of improving fundamental understanding of nanomaterial metrology and property assessment.

Cross-OU cooperation.

Public dissemination of results

Enable more in-depth analysis


Post RM Production Activities & Goals

Physico-Chemical Characterization

Size, Size Distribution Topology Molecular Weight Aggregation Purity Chemical Composition Surface Characteristics Functionality Zeta Potential Stability Solubility

Assay Cascade ProtocolsAssay Cascade ProtocolsPhysical – Physical – In VitroIn Vitro – – In VivoIn Vivo

http://ncl.cancer.gov/working_assay-cascade.asp

Public dissemination is a critical componentPublic dissemination is a critical component

NIST-generated documents


Future RM Plans

Next-Generation Gold Nanoparticles

Exploring new chemical routes for production of functionalized nanoparticles in collaboration with NCL. Some issues:

basic science underlying the technology stability packaging

Other Nanoparticles

Discussed options with potential partners including NTP (Nigel Walker) and FDA (Subhas Malghan)

Materials under consideration include silver, titanium dioxide


NIST Participants on Gold RM Project

Analytical Chemistry Division

Ceramics Division

Measurement Services Division

Metallurgy Division

Polymers Division

Precision Engineering Division

Process Measurements Division

Statistical Engineering Division

Standards for EHS Research Workshop, NIST, Sept. 12-12, 2007 Development and Production of Reference...

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