4. STSS_SOW RSC Automation.pdf

NCATS Scientific and Technology Support Services (STSS)

RSC Automation Support

Statement of Work (SOW)

1. Objectives

2. Background

3. Laboratory Management and Support:

4. Laboratory Automation and Equipment Support:

4.3.1. Liquid dispensation and handling system operation and support

4.3.2. Plate washer operation and support

4.3.3. Plate reader operation and support

4.3.4. Screening environment instrumentation operation and support

4.3.5. Staubli robotic arm operation and support

4.3.6. Other robotic arm operation and support

4.3.7. 3D Bioprinter operation and support

4.3.8. TekMatic Indigo Automated Chemical Reaction device operation and support

4.3.9. Reaction screening and MRV preparation support

4.3.10. Mass spectrometry operation and support

4.3.11. Microplate cleaning systems operation and support

4.3.12. Particle sorter operation and support

4.3.13. General laboratory instrumentation and equipment operation and support

5. Scientific Instrumentation Software as a Service (SaaS) and Desktop Support

6. High Content Assay Support

7. Collaborative Image Sharing and Visualization

8. Prototyping and Additive Manufacturing Support

9. Automated Platform Support

10. Advanced Automated Labware Handling

11. Distributed Automated Platform Support:

NCATS Scientific and Technology Support Services (STSS)

RSC Automation Support

Statement of Work (SOW)

1. Objectives

The National Center for Translational Sciences (NCATS) Information Technology Resources Branch (ITRB) Research Services Core (RSC) is seeking research support services to support the Automation group within the Division of Preclinical Innovation

(DPI).

The RSC provides compound library plating services for high-throughput screening at NCATS while supporting the maintenance and operation of laboratory instrumentation and processes. This SOW addresses two primary missions of the RSC: automation support and compound management. The automation experts at NCATS are responsible for the maintenance, operation and continuous improvement of a full range of laboratory instrumentation and processes. These automation engineers and machinists support NCATS activities in high-throughput screening and assay development and optimization. The compound management staff operate in partnership with the automation team. Using numerous types of sophisticated and automated sample management and liquid-handling instrumentation, these experts provide follow-up and dose-response library-plating services for NCATS screening activities.

This SOW addresses support for the RSC Automation Group, which includes:

• Assist in the development, maintenance, and operation of all fully automated screening systems at NCATS and our collaborative partners

• Assist in the development, maintenance, and operation of all screening instrumentation

• Assist in the development of next generation instrumentation for use within screening

• Evaluate emerging technologies and help to establish them at the institute

• Assist in the integration of all fully automated screening systems and instrumentation with secure, collaborative cloud environments

2. Background

The National Institutes of Health (NIH) is the Nation’s leading medical research agency and the primary federal agency whose mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability by supporting and making medical discoveries. NCATS is the only center at the NIH that focuses exclusively on all aspects of the translation of research with an innovative pipeline of treatment discoveries for all diseases. NCATS brings together a diverse group of scientists, including medicinal chemists, biologists, toxicologists, clinicians, and engineers to translate basic science conducted elsewhere into products and services that help improve people’s health and lives. NCATS’ mission is to improve health through smarter science that results in better treatments faster for all diseases, rare or common. The mission of RSC is to use high-throughput robots to help researchers run screening experiments quickly and efficiently, producing results in one week that would take a scientist 12 years to conduct manually. The RSC team works to facilitate these robots to test thousands of potential drugs and drug combinations, environmental chemicals, and other experimental compounds to gain insights about a wide range of human diseases.

The automation experts at NCATS are responsible for the maintenance, operation, and continuous improvement of a full range of laboratory instrumentation and processes. These automation engineers, machinists, software engineers, laboratory technicians, and others all support NCATS activities in high-throughput screening, assay development, and optimization for both fully integrated systems and all offline screening equipment. Given the nature of NCATS and the number of groups involved in screening, these duties require constant vigilance given the multitude of systems that run concurrently most days. NCATS has some of the most advanced early-stage drug discovery and translational laboratories in the world and is considered a flagship within the screening community. It is the responsibility of RSC to maintain and constantly advance that standard.

There is no other laboratory like it within the entire NIH intramural community, so prior experience at other NIH laboratories is typically NOT APPLICABLE as the scope, volume, and scientific applications required at NCATS are far beyond the typical wet lab at NIH.

3. Laboratory Management and Support:

3.1. The Contractor shall provide support for scientific laboratory research activities and laboratory management across all NCATS laboratories.

3.2. The Contractor shall assist in studies across various scientific disciplines.

3.3. The Contractor shall provide laboratory equipment management and support

3.4. The Contractor shall provide laboratory management support and training and ensure compliance with safety procedures.

3.5. Examples of work performed within this task include:

3.5.1. Ensure smooth running of laboratory operations by developing, communicating, and implementing laboratory SOPs. Provide expert advice, guidance, and assistance pertaining to laboratory operations and facility management

3.5.2. Assist with management of laboratory resources and ensure compliance with laboratory procedures. Develop recommendations to laboratory operations, management, and special requirements

3.5.3. Provide expert advice on safety issues and communicate safety practices and procedures to the laboratory staff

3.5.4. Collect and organize data; perform data analysis and

interpretation; prepare technical reports, summaries, and protocols; interpret and evaluate results of experiment

3.5.5. Review and research the proper handling and methods of utilization for different biological and chemical materials in regular use in the lab

3.5.6. Prepare various media, stock supplies, and other reagents for use in the laboratory

3.5.7. Assist in the analysis and interpretation of data and prepare summaries of laboratory findings to be used in reports and scientific papers

3.5.8. Provide training to students and other laboratory personnel in the performance of specialized procedures and techniques

3.5.9. Perform quality control of the laboratory to include upkeep and routine maintenance; order and maintain laboratory supplies, including chemicals, biological materials, liquid nitrogen, etc.

3.5.10. Perform a wide variety of complex procedures and techniques including but not limited to cell culture, clinical/diagnostic microbiology, DNA isolation, DNA purification, gene cloning

3.5.11. Calibrate and operate a variety of laboratory instruments used to perform tests, analyses, and other laboratory procedures

4. Laboratory Automation and Equipment Support:

4.1. The Contractor shall provide support for scientific laboratory automation and equipment/instrumentation across all NCATS laboratories. Support generally falls within five key laboratory support functions that may be required for any particular device.

4.1.1. Installation functions (e.g. installation, setup, initial configuration, integration, etc.)

4.1.2. Use functions (e.g. operation, preparation, calibration, validation, programming, reconfiguration, etc.)

4.1.3. Support functions (e.g. technical help desk, scientific (subject matter) support, training, etc.)

4.1.4. Maintenance functions (e.g. routine maintenance, repair, legacy support, etc.)

4.1.5. Enhancement functions (e.g. hardware and software modifications, etc.)

4.2. The Contractor shall provide additional support for legacy equipment that is no longer supported by the manufacturer that may include troubleshooting and repairing hardware (including mechanical, electrical, and pneumatic problems), fabrication of replacement parts, software troubleshooting and repairs, and other functions that may be required to support continued operation.

4.2.1. Contractor shall understand and make modifications to legacy Visual Basic, C++, LabView, and other obsolete code associated with legacy instruments.

4.2.2. Examples of legacy instruments include original BioRAPTRs, GNF pintools, EDC ATS-100s, and others that are critical to many NCATS laboratory operations.

4.3. Equipment to be supported includes, but is not limited to:

4.3.1. Liquid dispensation and handling system operation and support.

4.3.1.1. Contractor shall operate, perform validation procedures, and perform maintenance on liquid dispensation and handling systems:

4.3.1.1.1. Low volume liquid dispensation systems

including legacy BioRAPTRs; BioRAPTR IIs; Certus Flex dispensers;

4.3.1.1.2. multichannel pipette systems including Beckman BiomekFX, I5, and I7, PerkinElmer Janus, Tecan EVO, Agilent VPrep, and others;

4.3.1.1.3. Pintools including GNF, or FujiFilm Wako

Automation

4.3.1.1.4. acoustic liquid handlers such as EDC ATS-100 or LabCyte Echo;

4.3.1.1.5. other off-line liquid handling systems.

4.3.1.2. The Contractor shall troubleshoot and repair software, mechanical, electrical, and pneumatic problems with legacy instruments (such as the original BioRAPTRs, GNF pintools, EDC ATS-100s, and others) that are no longer supported by the manufacturer, but these instruments are critical to many NCATS laboratory operations.

4.3.1.3. The Contractor shall understand and make modifications to legacy Visual Basic, C++, LabView, and other obsolete code associated with older instruments such as those referenced above.

4.3.2. Plate washer operation and support.

4.3.2.1. Contractor shall operate, perform maintenance, and perform validation procedures on plate washers such as the Biotek EL406, BioSpa, BlueCatBio Centrifugal Blue Washer, legacy GNF and FujiFilm Wako Automation plate washers, and others.

4.3.2.2. These devices are critical for cell staining applications used for high content screening. Contractor shall provide direct support including assay validation, optimization, and execution.

4.3.2.3. Routine maintenance is a requirement for many of these systems given the nature of their operation and dealing with biological reagents that can be difficult to clean. Contractor shall support routine maintenance, and shall support NCATS efforts to automate maintenance.

4.3.3. Plate reader operation and support.

4.3.3.1. Contractor shall operate and perform maintenance and validation procedures on plate readers, such as EnVision, Opera Phenix and Operetta CLS, BMG Pherastar, SPTLabtech Acumen Explorer and MirrorBall, Molecular Devices ImageXpress and FLIPR Tetra, MSD QuickPlex SQ120, Sector S600, the legacy PerkinElmer (PE) ViewLux, and others.

4.3.3.2. Readers such as the legacy ViewLux are no longer supported by the manufacturer, but these instruments are critical to many NCATS laboratory operations. Contractor shall provide all support for legacy instruments, to include troubleshooting and repairing mechanical, electrical, cooling components, and imaging problems with the instrument, and obtaining and replacing damaged components as required.

4.3.3.3. Contractor shall provide direct support in setting up assay specific protocols for each reader listed. Note that this is a challenging problem especially with regards to high content readers such as the Opera Phenix, Operetta CLS, ImageXpress, and imagers in general. Contractor shall be familiar with the variety of detection modalities each reader provides.

Contractor shall be able to choose the appropriate detection instrument, the optimal magnification to be used during the measurement, the fluorescence channel settings, the optimal signal to noise ratio, the level of image sampling (2D or 3D if the reader supports confocal imaging), and a variety of other considerations.

4.3.4. Screening environment instrumentation operation and support.

4.3.4.1. The Contractor shall operate, program, and perform

maintenance as required on lab instrumentation typically used in a screening environment, such as centrifuges, high precision scales, Agilent PlateLoc plate sealers, Brooks XPeel plate seal removers, and other instrumentation as required.

4.3.4.2. As noted above, it is most common that most of the

equipment is not covered under a service contract. In such cases the Contractor shall repair the equipment onsite.

4.3.5. Staubli robotic arm operation and support.

4.3.5.1. Contractor shall operate, program, and perform maintenance as required on Staubli robotic arms (TX40, RX160) and CS8C controllers, including the replacement of electrical, mechanical, and pneumatic components, with assistance from the manufacturer as required.

4.3.5.2. Contractor shall configure robot cells using Staubli Robotics Suite (SRS) Developer Studio software.

4.3.5.3. Contractor shall use the Staubli VAL 3 programming language, including using a variety of communication protocols such as RS-232, TCP/IP, and others.

4.3.6. Other robotic arm operation and support.

4.3.6.1. Contractor shall operate, program, and perform maintenance as required on Precise Automation PF400/300, Universal Robots UR5, and Mecademic Meca500 robotic arms.

4.3.6.2. Contractor shall program these robotic arms to perform a variety of laboratory automation tasks.

4.3.6.3. Contractor shall identify and recommend a variety of gripper types depending upon the types of samples to be handled.

4.3.6.4. Contractor shall integrate these, and other robotic platforms, with distributed I/O systems including but not limited to analog inputs and outputs, digital input and outputs, waveform generators, and other industrial engineering protocols.

4.3.7. 3D Bioprinter operation and support

4.3.7.1. Contractor shall operate, program, perform maintenance, modify, and enhance several RegenHu 3D bioprinters, including the design, fabrication, and integration of custom labware to support specific bioprinting applications.

4.3.7.2. Contractor shall design prints to be printed on the bioprinters.

4.3.7.3. Contractor shall use a variety of print heads, including pneumatic, linear actuated mechanical displacement, solenoid valve-based cell dispensing, electrospinning, and other technologies as required.

4.3.7.4. Contractor shall maintain and repair, including all components such as limit switches, sensors, electrical and mechanical components, software issues, and others. The manufacturer is not based within the United States and has limited ability to respond to printer issues quickly, either onsite or remotely given the time difference. The time it takes to prepare samples to print can take weeks, if not months, based upon the type and volume of cells to be produced to populate a 96 well plate, meaning any issue that arises with the instrument must be handled IMMEDIATELY. A service call typically DOES NOT SUFFICE, as months of tissue culture labor, consumable, and reagent cost can be lost if the printer is not functioning properly. The contractor shall be able to provide a response time measured in MINUTES to repair the printer as quickly as possible.

4.3.7.5. Contractor shall have the capability to design, manufacture, implement, and test custom or modified labware to be used for printing on the RegenHu printer. These custom parts are application specific and must typically be designed to also allow to be incorporated in high content readers such as the Opera Phenix or ImageXpress.

4.3.8. TekMatic Indigo Automated Chemical Reaction device operation and support.

4.3.8.1. The contractor shall operate, program, perform maintenance, modify, and enhance TekMatic Indigo Automated Chemical Reaction devices. This device is one of the most critical components of the NCATS ASPIRE (A Specialized Platform for Innovative Research Exploration) program, as automated chemical synthesis (ACS) is a foundational capability. The rest of the program has no chance to succeed if this device is not fully operational, making this a critical instrument for the contractor to provide RSC support for.

4.3.8.1.1. The Indigo is an incredibly complicated device

comprised of 8 parallel channels with independent control of heating, cooling, stirring, and reflux reactions in standard 2-5mL or 20mL Microwave Reaction Vials (MRV). Each channel, or reactor, is independently controlled and can reach temperatures from -40°C to 150°C, starting from ambient, and can be pressurized up to 30 bar or down to 300 mbar.

4.3.8.2. The Contractor shall create reaction templates that can be transferred to the device to run automated chemical synthesis routines.

4.3.8.3. The Contractor shall analyze generated logs for temperature and pressure to track reaction performance.

4.3.8.4. The Contractor shall develop, run, and analyze Benchmark Reactions used to characterize the reactor performance, including but not limited to:

4.3.8.4.1. Amidation

4.3.8.4.2. Suzuki Coupling

4.3.8.4.3. Buchwald-Hartwig

4.3.8.4.4. SNAr

4.3.8.4.5. Reductive Amination

4.3.8.4.6. Esterification

4.3.8.4.7. Grignard Reaction

4.3.8.4.8. Carbonyl Reduction

4.3.8.4.9. Alcohol Oxidation

4.3.8.4.10. N-Sulfonylation

4.3.8.4.11. N-Alkylation

4.3.8.4.12. O-Alylation

4.3.8.5. The Contractor shall develop, run, and analyzer complex cleaning protocols to perform in each lane upon completion of a reaction.

4.3.8.6. The Contractor shall work closely with RSC staff and the manufacturer to determine points of failure and suggest possible improvements for all components of the reactor, be they electrical, mechanical, liquid path, cooling system, and others. Although this is sold as a fully operational instrument, the reality is it is very much in a beta state, requiring modifications and optimizations to a variety of components.

4.3.8.7. The Contractor shall work closely with the manufacturer to help develop, test, validate, and improve a web-based GUI to control the reactor in a manual or automated fashion.

4.3.8.8. The Contractor shall integrate the reactor with other components of an automated chemistry workflow, including but not limited to MRV reactant preparation systems, analytical chemistry modules, and product storage systems.

4.3.9. Reaction screening and MRV preparation support

4.3.9.1. The Contractor shall operate, program, perform maintenance, modify, and enhance instrumentation and software associated with reaction screening, high-throughput reaction screening, and MRV preparation workflows.

4.3.9.1.1. Reaction screening may include high

throughput reaction screening of catalysts for cross-coupling or photochemical reactions, or for determining optimal reaction conditions.

4.3.9.1.2. The Contractor shall develop, evaluate, and

optimize automated chemical powder dispensers utilizing the following components and devices. This includes complete familiarity with the associated software used to control the devices, including the ability to integrate it with other devices when appropriate:

4.3.9.1.2.1. Chemspeed Gravimetric Dispensing

Units (GDU):

4.3.9.1.2.1.1. SWILE

4.3.9.1.2.1.2. GDU-Pfd

4.3.9.1.2.1.3. SMOLE prefilled chemical vials

4.3.9.1.2.2. Mettler Toledo XPR Automatic Balance

with sample changer

4.3.9.1.2.3. Unchained Labs Junior

4.3.9.1.3. The Contractor shall use the Unchained Labs

Junior to perform solid loading, liquid handling, stirring/heating, reaction execution, and other workflows from a local or remote setting.

4.3.9.1.4. The Contractor shall perform reaction screening

experiments in a glovebox (MBraun, etc.) under inert conditions utilizing libraries of cross-coupling catalysts and UV plates for photochemistry when required.

4.3.9.1.5. The Contractor shall use a Waters Acquity UPLC

to perform analysis on executed reactions.

4.3.9.1.6. The Contractor shall install, configure, deploy, maintain, and operate the Virscidian Analytical Studio

4.3.9.1.6.1. The Contractor shall connect different

analytical instrument types directly to Virscidian Analytical Studio to allow for direct data ingestion to the platform

4.3.9.1.6.2. The Contractor shall use Virscidian

Analytical Studio for data analysis and report generation

4.3.9.1.7. The Contractor shall integrate Virscidian

Analytical Studio with the Waters UPLC, allowing for the automatic upload of liquid chromatography (LC) and Mass Spectrometry (MS) directly from the instrument to identify product, starting materials, and byproduct.

4.3.9.1.8. The Contractor shall use the Virscidian

Analytical Studio to export results as a colorimetric graph and excel file as required.

4.3.9.1.9. Upon identification of reactions to perform, the

Contractor shall use the Unchained Labs Junior to prepare MRVs for loading into the Indigo reactor.

4.3.10. Mass spectrometry operation and support.

4.3.10.1. The Contractor shall operate and perform maintenance and validation procedures on Sciex QTRAP 6500 Mass Spectrometer, including peripheral devices such as high-speed pumps, autosamplers, and others.

4.3.10.2. The Contractor shall support the use of the Sound Analytics LeadScape and LS-I platform with the 6500.

4.3.10.3. The Contractor shall support Acoustic Ejection Mass Spectrometry (AEMS) which is the use of an acoustic dispenser (such as the EDC ATS-100) to directly inject a sample into the Sciex 6500 Mass Spectrometer via an open port interface

(OPI).

4.3.10.4. The Contractor shall provide support for mass spectrometry-based assay development and execution. Note that this is an emerging technology at NCATS and other laboratories that requires direct experience for adequate support.

4.3.11. Microplate cleaning systems operation and support

4.3.11.1. The Contractor shall operate and perform maintenance and validation procedures on IonField Systems PurePLATE microplate cleaning system (MCS) and Grenova TipNovus systems to clean used microplates and pipette tips to support sustainable laboratory activities at NCATS.

4.3.11.1.1. NCATS has a proven track record for the

development and support of sustainable laboratory practices, such as creating innovative approaches for cleaning and reuse of microplates and pipette tips. The Contractor shall support and improve NCATS’ development and implementation of these techniques to reduce the amount of laboratory waste generated by NCATS.

4.3.11.1.2. The Contractor shall analyze, evaluate, experiment, and implement new techniques related to the reduction or re-use of laboratory consumables, including biological and chemical reagents.

4.3.12. Particle sorter operation and support.

4.3.12.1. The Contractor shall operate and perform maintenance and validation procedures on the UnionBio COPAS Vision particle sorter with real-time brightfield imaging.

4.3.12.2. The Contractor shall provide all support for this complicated piece of instrumentation, including the design of custom labware to support the dispensing of sorted particles (organoids, cell spheroids, etc.) into specific regions of labware such as transwell membrane plates.

4.3.13. General laboratory instrumentation and equipment operation and support.

The Contractor shall:

4.3.13.1. Assess, maintain, perform repairs and validation on hundreds of pieces of existing equipment throughout the facility.

4.3.13.2. Perform placement, setup, and validation of new equipment.

4.3.13.3. Maintain and acquire tools and supplies for repair tasks.

4.3.13.4. Work with vendors to recommend replacement parts for equipment; maintain stock.

4.3.13.5. Work with vendors to make recommendations to NCATS on new laboratory equipment.

4.3.13.6. Train laboratory staff on the use and care of equipment.

4.3.13.7. Perform basic troubleshooting and correction of minor online screening system failures, including responding to errors that occur during off hours.

4.3.13.8. Ensure proper care in the use and maintenance of laboratory equipment and supplies.

4.3.13.9. Place service calls for scientific equipment in the laboratory.

4.3.13.10. Collaborate with other laboratory managers on other laboratories.

4.3.13.11. Perform troubleshooting and correction of laboratory, building and screening system component; diagnose problems down to the component level; respond to errors.

4.3.13.12. Design, fabricate, and install various components and fixtures to be used within the laboratory or automated screening platform setting.

5. Scientific Instrumentation Software as a Service (SaaS) and Desktop Support

5.1. Contractor shall provide knowledgeable, customer-focused support for day-to-day interactions with NCATS scientists with the intent of supporting all laboratory instrumentation in use at the center.

5.1.1. There are currently over 400 pieces of instrumentation at NCATS that have a dedicated scientific PC connected to it with operating systems ranging from multiple Windows versions (2000 to 11) to a variety of Linux flavors (Debian, Ubuntu, Mint, etc.). This instrumentation ranges from next generation sequencers, liquid handlers, low volume liquid dispensers, plate readers and a variety of others. Much of this instrumentation is essential to NCATS meeting its scientific mission and some of it requires extended operation across days or even weeks to perform a variety of experiments without interruption.

5.1.2. Each piece of this instrumentation typically comes with a specific installation configuration that has been validated by the vendor.

Any changes to this configuration can result in inconsistent behavior or even the failure to operate. This configuration in many cases deals specifically with the means of instrument communication, be it via a serial port (RS-232), TCP/IP, CAN bus, Ethernet/IP, USB (2.0 and 3.0), OPC and others. The nature of these means of communication between the connected PC and the instrument typically requires less stringent security controls to ensure continuous operation of the device. This communication coupled with a standard configuration is prone to failure if updated or patched as many patches deal with communication vulnerabilities. Correcting them by disabling necessary protocols requires specific expertise in the establishment, maintenance, and monitoring of a dedicated scientific network to sequester these instruments from the primary NIH network as they cannot be held to the same security standard.

5.1.3. The Contractor shall provide staff who understand the importance of continuous operation of instrumentation coupled with secure collaboration. Another recent development making this even more challenging is that more and more instrumentation that generate large amount of data (terabytes or even petabytes) are beginning to have a direct connection to the cloud, both for data storage but also to enable direct access to scientific Software as a Service (SaaS). To date, these are primarily next generation sequencers, high content plate readers, mass spectrometers and soon to be others. This requires not only custom and specific configurations for instrument connectivity and data transfer between the instrument and the controlling PC, but also an external cloud connection that meets all security requirements while maintaining cloud connectivity.

5.1.4. The contractor MUST meet all capabilities listed above and provide references of past work, in addition to the following objectives:

5.1.5. The Contractor shall install instrumentation with custom configurations specified by the vendor

5.1.5.1. The Contractor shall consult with NCATS scientific staff to determine appropriate system configuration where applicable, to ensure that the controlling PC will function properly both with the instrument or system it is connected to while also allowing NIH network access when required

5.1.5.2. The Contractor shall work with NIH procurement specialists to consult on system specifications when possible, including the possibility of sending pre-configured PCs to the vendor for installation of custom software

5.1.5.3. The Contractor shall have DIRECT experience in ensuring that tools such as TeamViewer, Bomgar, etc. can be installed and configured to allow for remote support as required.

5.1.5.3.1. This can sometimes require extensive work with

infrastructure, network, and security engineers.

5.1.6. The Contractor shall support connecting instrumentation across physical and logical boundaries (e.g. multiple NIH institutes and centers (IC); academic research centers; etc.) to allow for remote operation, monitoring, and data ingestion. This includes, but is not limited to:

5.1.6.1. Configuring controlling instrument PCs with appropriate permissions, GPOs, and protocols to allow for remote access in a secure fashion

5.1.6.2. Familiarity with desktop support tools (such as Bomgar) to allow remote access and troubleshooting

5.1.6.3. Work with network and security engineers to enable

appropriate firewall access between ICs

5.1.6.4. Work with security and logging engineers to ensure all applicable logs are collected and stored

5.1.6.5. The Contractor shall connect PE Opera Phenix plate readers between ICs in a secure fashion to enable instrument operation while saving data across ICs boundaries to be stored on NCATS servers

5.1.7. The Contractor shall connect instrumentation to vendor specific cloud environments for data storage, processing, and electronic laboratory notebook (eLN) record keeping. The Contractor shall:

5.1.7.1. Work with network and security engineers to enable

appropriate firewall access between NCATS and the cloud provider.

5.1.7.2. Work with security and logging engineers to ensure all applicable logs are collected and stored.

5.1.7.3. Work with the cloud providers to enable single sign on (SSO) with NIH credentials.

5.1.7.4. Support users with the operation of cloud-based data analysis tools.

6. High Content Assay Support

NCATS research groups extensively utilize automated microscopy equipment and high-content analysis (HCA) methods for cell-based drug discovery campaigns. These technological approaches enable the high throughput testing of novel pharmaceutical compounds in mammalian cellular model systems. HCA approaches rely on computational algorithms to measure changes in cellular behavior that are recorded in digital micrograph images. Typical HCA screening productions runs generate and analyze a million digital images per day. RSC provides support for all levels HCA initial development and execution of large-scale screening campaigns. This includes maintenance of automated microscopy equipment, consulting in the optimal use of this equipment, maintenance of commercial data analysis software and development of custom analysis algorithms, primary automated image analysis (using commercial software or custom algorithms), secondary statistical analysis, visualization, and interpretation of results. Along with other orthogonal experimental approaches, the HCA projects push forward the primary institutional goal of NCATS, which is to increase the rapid translation of fundamental biological understanding into clinical therapies that directly benefit patients. The contactor will be required to support RSC in all aspects of high content assays as described below:

6.1. The Contractor shall support biological sample preparation, including but not limited to:

6.1.1. Cell culture miniaturization

6.1.2. Cell fixation and staining, including the selection of dyes, labels, and reagents

6.1.3. Fluorescent protein selection

6.1.4. Positive and Negative assay control conditions

6.2. The Contractor shall support microscopy digital image acquisition, including but not limited to:

6.2.1. Instrument selection

6.2.2. Optimal magnification and objective selection

6.2.3. Fluorescence channel settings

6.2.4. Optimal Signal to Noise ratio

6.2.5. Live-Cell imaging considerations (photobleaching, etc.)

6.2.6. Level of image sampling (2D vs 3D)

6.2.6.1. Number of 2D XY fields per sample

6.2.6.2. Number and spacing of Z planes for 3D images

6.2.6.3. Time series parameters (duration, frequency, etc.)

6.3. The Contractor shall support primary image analysis with both fixed model-based cellular image analysis (automatic thresholding segmentation, watershed segmentation, etc.) and deep-learning based cellular image analysis (pixel classification, object detection, semantic segmentation, etc.). The types of analyses to be performed are listed below, including but not limited to:

6.3.1. Hierarchical image segmentation

6.3.1.1. Well regions, multicellular structures

6.3.1.2. Individual cells

6.3.1.3. Individual subcellular structures

6.3.2. Diverse morphology types, 2D or 3D segmentation

6.3.2.1. Epithelial, fibroblastic, or neuronal cell monolayer

6.3.2.2. Epithelial, fibroblastic, or neuronal organoids

6.3.2.3. Vascular engineered tissues

6.3.3. Extraction of numerical features from segmented structures

6.4. The Contractor shall provide secondary numerical analysis including but not limited to:

6.4.1. Hierarchical summary statistics

6.4.1.1. Well regions, multicellular structures

6.4.1.2. Individual cells

6.4.1.3. Individual subcellular structures

6.4.2. Multiparametric phenotype characterization: analysis within sample and/or between samples

6.4.2.1. Feature reduction

6.4.2.2. Supervised classification/learning

6.4.2.3. Unsupervised classification/learning

6.4.3. Classical high throughput screening analytics

6.4.3.1. Dose response curve fitting

6.4.3.2. ‘Hit compound’ selection/ranking

6.5. The Contractor shall provide data visualization where required, including but not limited to:

6.5.1. Images with segmented regions of interest (ROI), and single ROI numerical values

6.5.2. Single parameter or multiparameter plots such as:

6.5.2.1. Heatmaps

6.5.2.2. Scatter plots

6.5.2.3. Histograms

6.5.2.4. Custom

6.5.3. 2D or 3D graphing of data reduction outputs

6.5.4. Display of classification results

6.6. The Contractor shall create image analysis pipeline scripts in multiple programming environments such as MATLAB, R, and Python to support all requirements as described in 6.3 and 6.4 for primary image analysis and secondary numerical analysis respectively.

6.7. The Contractor shall use the following commercial GUI-based software packages for customized automated cellular image analysis as described in sections 6.3 and 6.4, including:

6.7.1. PerkinElmer Columbus server-based software platform

6.7.2. PerkinElmer Harmony workstation-based software platform

6.7.3. Molecular Devices MetaXpress workstation-based software platform

7. Collaborative Image Sharing and Visualization

Multiple scientific programs at NCATS generate large amounts of imaging data from several sources including high content screens (transmitted and multi-channel fluorescence, 2D and 3D screens, etc.), and tissue sectioning (whole slide hematoxylin and eosin staining, and immunohistochemistry, etc.). The challenge that NCATS faces is that it performs hundreds of assays a year, where each assay ranges from a few dozen plates to hundreds. To truly transform translational medicine NCATS needs to not just generate this data but share it with the community. Given that nearly every project at NCATS is part of a collaboration, it is not enough to simply share the data internally, but it requires that it is also shared with our collaborative partners and the general scientific community where required. Given the collaborative nature of science, it is also a requirement that NCATS share not only our own data, but other data sets as generated by the community.

7.1. To achieve these objectives, NCATS requires a platform that is:

7.1.1. Fully open source, written in web native languages, and have not only the code but extensive deployment documentation available.

7.1.2. Able to integrate with the NCATS authentication framework;

Unified NCATS Auth (UNA); for secure and facile data ingestion

7.1.3. Scalable and performant in a web browser even when interacting with datasets with 100s of terabytes worth of data

7.1.4. Flexible and can handle data from both high content screening plates (with well densities from 6, 12, 24, 96, 384, 1536, and beyond) and whole slide pathology

7.2. Currently, NCATS has 10s of terabytes of image-based data that has already been published and no easy way to share these with the scientific community.

To enable organization, visualization, and sharing data at this level, NCATS requires this platform to have six key features:

7.2.1. A web-based application that allows for simple GUI based organization, metadata viewing, search, filtering, and download of large amounts of image-based data

7.2.2. Robust 2D and 3D data visualization and interaction web applications that allow for data visualization, metadata overlay (such as a chemical structure of a hit compound in a high content screen), and real-time interactions with image data such as zoom, pan, and rotate.

7.2.3. Well documented, standardized, and programmatic access to data via REST APIs and CLI tools where appropriate

7.2.4. Detailed tracking of image/data access, download, and visualization to be to show the impact of the portal and enable infrastructure planning

7.2.5. Robust and automated data ingestion pipelines to standardized image transfer, format, appearance, metadata, and schema to adhere to FAIR data principles

7.2.5.1. These pipelines can initiate directly from an acquisition device directly, such as the automatic ingestion of images directly from an Opera Phenix high content reader. Direct experience with automated ingestion directly from instruments is REQUIRED, as the ideal time to capture data and associated metadata is at the time an experiment is run, not after the fact.

7.2.6. Handling of hierarchical permissions so that sensitive data, such as pre-publication data, can be kept private, but that data that is ready for the community can easily be shared

8. Prototyping and Additive Manufacturing Support

Given the nature of multiple programs at NCATS being on the leading edge of research and engineering areas, such as 3D bioprinting, automated chemical synthesis, acoustic ejection mass spectrometry, automated tissue culture, and others where commercial products are not readily available to fill critical gaps, NCATS has come to rely more and more on prototyping, additive manufacturing, and reverse engineering. RSC has numerous examples of how these capabilities have greatly benefited programs such as the creation of customized labware tailored to the needs of specific projects or creating parts with high chemical resistance which allow them to withstand harsh test conditions. The ability to utilize technologies to create components allowing for complex geometries while providing unique material properties gives RSC the capabilities to rapidly develop prototypes and parts to solve problems that we would not otherwise be able to do so. The ability to measure and generate 3D geometry based off commercial products such as flasks, vials, and other consumables and to then create custom parts to enhance existing or create new capabilities for a wide variety of equipment and instrumentation has been transformative. These capabilities have become a core offering of RSC, and the contractor must have direct experience with a wide variety of equipment and techniques to support NCATS prototyping and fabricating capabilities.

8.1. The Contractor shall use SolidWorks, Slicer, and other computer assisted design (CAD) software packages to generate designs that can then be transferred to a variety of 3D printing devices for fabrication.

8.2. The Contractor shall work with a wide variety of labware types, such as microplates, vials, tissue culture flasks, and others as required to augment existing or create replicates with modifications to their geometry or material properties to facilitate enhancements or new capabilities to a scientific process or workflow.

8.2.1. Examples of this can include enhancements made to cell culture insert plates to allow for increasing the volume of cell media that can be used in the carrier plate or the creation of a re-usable tissue culture flask for use in an automated platform to greatly reduce the number of flasks required for a process to run.

8.3. The Contractor shall incorporate rapid prototyping techniques to augment or make improvements to a wide variety of instruments, automated platforms, facilities, and general laboratory equipment as required.

8.3.1. Examples of this can include enhancements made to instruments to allow for the use of custom labware for advances measurements, modifying plate nests and other fixtures to facilitate integration with robotic systems, or other general enhancements to improve operations and laboratory processes.

8.4. The Contractor shall have direct experience with the following equipment including the configuration, setup, operation, maintenance, and enhancement when required.

8.4.1. 3DGence F421 high-performance material (PEEK, CF-PEEK, Ultem) dual extrusion 3D printer with 1M/s travel speed and industrial grade part production

8.4.2. Keyence VL570 3D Scanner/CMM with high accuracy and 2µm repeatability

8.4.3. Diabase H5-400 5-Axis CNC and FDM Hybrid

8.4.4. 3Devo GP-20 Hybrid and Composer 450 3D print recycling system comprised of a shredder, granulator, dryer, and filament machine to complete recycling of end-of-life printed parts, failed prints, or custom material compositions

8.4.5. Yamato DKN602C programmable lab oven capable of preparing & annealing high performance materials such as PEEK and other temperature critical materials for 3D printing

8.4.6. 3DGence Clean Station SRS support cleaning station large format agitation & solution-based 3D printed support removal system great for External and internal geometry both small to medium in size

8.4.7. Oryx scaWaterjet Water Jet Cabinet high pressure 3D printed support removal cabinet for rapid large scale support removal

8.4.8. Mitutoyo 570-313 height gage

9. Automated Platform Support

The Contractor shall provide support for multiple automated platforms, including high throughput screening, compound management, automated tissue culture, automated chemical synthesis (ACS), and others. Examples of work performed within this task include the following:

9.1. Develop, operate, enhance, and maintain custom automation platforms to perform high throughput screening, automated chemical reactions, and other experimental modalities comprised of protocol development, experiment and device scheduling, error recovery, and autonomous operation utilizing commercial and custom software which is capable of both manual and automated operation

9.1.1. Must provide the capability to actively monitor events in real time and to control the provided scheduling software through external applications

9.1.2. Must allow multiple processes to run in parallel

9.1.3. Must allow the programmatic launch of new processes

9.1.4. Must be asynchronous in operation

9.1.5. Must provide the capability to communicate with external applications to coordinate tasks and record results including such endpoints to a variety of cloud storage options (AWS, Google Cloud

Platform (GCP), Azure, etc.), databases (AWS RDS, NoSQL, PostgreSQL, Oracle, etc.), distributed office applications (Office 365, Google Sheets, etc.), open standard messaging protocols such as Advanced Messaging Queuing Protocol (AMQP) and machine-to-machine connectivity protocols such as MQ Telemetry Transport (MQTT) (often referred to as the ‘Internet of Things (IoT)’)

9.1.6. Must be able to incorporate AI/ML driven experimentation, such that the automated platform can communicate with external informatics environments in a bi-directional fashion.

9.2. Develop hardware drivers to integrate instrumentation onto automated platforms, including API implementation for external control and monitoring, where required.

9.3. Work with assays performed on various FujiFilm Wako Automation, High Resolution Biosystems (HRB), Agilent BioCel, and LabCyte Access automation platforms.

9.3.1. For FujiFilm Wako Automation, the Contractor shall operate both current and legacy versions of their Director software.

9.3.1.1. The Contractor shall set up all peripheral devices on the screening platform in advance of an assay.

9.3.1.2. The Contractor shall create custom Method files to execute an assay on the platform.

9.3.1.3. The Contractor shall use custom developed applications to initiate assays on the platform and should be familiar with monitoring the system for errors during operation and with proper error recovery techniques for both peripheral devices and platform components, such as the robot arm(s).

9.3.1.3.1. Peripheral devices include, but are not limited

to, custom GNF and FujiFilm Wako dispensers and pintools, legacy BioRAPTR dispensers, Beckman BiomekFX multichannel pipette systems, BMG Pherastar, Hamamatsu FDSS, PE Envision and Viewlux plate readers, Agilent VSpin centrifuges and PlatLoc plate sealers, Genova TipNovus, Brooks XPeel seal removers, EDC ATS-100 and LabCyte Echo acoustic transfer devices, and others.

9.3.1.3.2. The Contractor shall response to plate handling

errors on the system as necessary, requiring the manual operation of robotic arms while adhering to all safety precautions.

9.3.1.4. For legacy versions of Director, the Contractor shall control and monitor the system via a vendor provided ActiveX control.

The Contractor shall use a vendor provided .NET component for programmatic Method file generation to enable dynamic screening.

9.3.1.5. For legacy versions of the Director involved in hit picking operations, the Contractor shall generate custom pick lists from source sample plates to be loaded on the BiomekFX for execution.

9.3.1.6. For current versions of Director, the Contractor shall integrate the scheduling software for remote monitoring and control via either Microsoft SignalR or WebSocket.

9.3.1.7. Independent of version, the Contractor shall save all data generated during assays in real time to a NCATS provided database for historical record keeping. This includes data related to the execution of assay specific steps, including all resultant data files generated by plate read operations.

9.3.1.8. The Contractor shall integrate Director with external applications capable of communicating with other messaging systems such as RabbitMQ, IoT frameworks, Google Workspace, etc. to enable direct control of the high throughput screening system via remote locations.

9.4. For HRB systems, the Contractor shall use proprietary Cellario software to design and execute runs. The Contractor shall create custom software to access the underlying database architecture of Cellario to initiate and monitor custom experiments.

9.5. For Agilent BioCel systems, the Contractor shall work with functional systems capable of performing high throughput screens or plate stamping or reformatting routines.

9.5.1. The Contractor shall configure, operate, maintain, troubleshoot, and recover from errors when required, all peripheral devices on the system, including but not limited to:

9.5.1.1. Precise Direct Drive robotic arms

9.5.1.2. BioCel I/O Interface

9.5.1.3. Agilent PlateLoc Microplate Sealer

9.5.1.4. Agilent Labware Stackers

9.5.1.5. Liconic Plate Incubators

9.5.1.6. BioCel Plate Hub Carousel

9.5.1.7. Agilent Microplate Centrifuge

9.5.1.8. Brooks XPeel microplate seal remover

9.5.1.9. Agilent Vertical Pipetting Station (VPrep)

9.5.1.9.1. The Contractor shall swap between 96 and 384

tip heads as required

9.5.1.9.2. The Contractor shall calibrate heads as required

9.5.1.9.3. The Contractor shall replace damaged or non-

functional tip positions

9.5.2. The Contractor shall use VWorks software to:

9.5.2.1. Setup the BioCel system

9.5.2.2. Define and modify labware to be run on the system

9.5.2.2.1. The Contractor shall add new labware as

required, including all required dimensions and offsets, as misconfigured labware is a common cause of plate handling errors on the system

9.5.2.3. Create protocols

9.5.2.3.1. The Contractor shall create custom protocols to

perform plate stamping and library reformatting operations

9.5.2.4. Run, pause, monitor, handle errors are required, and stop protocols

9.5.2.4.1. The Contractor shall respond to errors during a

protocol run as required, including all system components such as plate storage and robotic arms for plate handling, and including all peripheral devices on the platform. The system at NCATS typically handles incredibly precious libraries of samples, so a near immediate response to errors is required, as any delay can result in the loss of thousands of dollars in reagents. NCATS has not had a service contract on this platform in close to a decade as the original vendor no longer supports the product, so the Contractor shall respond to and correct errors as quickly as possible.

9.6. For LabCyte Access systems, the Contractor shall work with functional systems capable of performing high throughput screens, plate reformatting, and the generation of assay ready plates in single or multiple agent routines.

9.6.1. The Contractor shall configure, operate, maintain, troubleshoot, and recover from errors when required, all peripheral devices on the system, including but not limited to:

9.6.1.1. Precise Direct Drive robotic arms

9.6.1.2. PLC Interface for I/O control

9.6.1.3. Agilent PlateLoc Microplate Sealer

9.6.1.4. Liconic Plate Incubators

9.6.1.5. BioCel Plate Hub Carousel

9.6.1.6. Agilent Microplate Centrifuge

9.6.1.7. Brooks XPeel microplate seal remover

9.6.1.8.