OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): Combat Casualty Care OBJECTIVE: Development of a portable, high throughput, handheld device that characterizes platelet contractility (a measurement of platelet functional viability) as a transfusion release criterion for military and civilian blood banks and transfusion services. DESCRIPTION: Conventional assays intended to characterize platelets in vitro fail to provide a comprehensive assessment of platelet function, only capturing information about adhesion, aggregation, or storage contamination status in platelet blood products (e.g. pH, blood cultures). These deficiencies are exacerbated in traumatically injured patients. Information about platelet metabolism and signaling is limited in current platelet function tests. Thromboelastography (TEG) is low throughput and measures clot properties; however, information about platelet function may be missed.1 Light transmission/impedance aggregometry are susceptible to analytical variables, require high sample volume, and are manually intensive and time-consuming.2,3 Platelet contraction requires all aspects of cell physiology in order to successfully cause clot retraction.4 However, current methods to measure clot retraction, such as visual observation or laboratory-based assays, are limited by their complexity, high costs, and the need for trained personnel, preventing their use in time-sensitive or resource-limited settings; additionally, these methods for measuring clot retraction do not provide quantitative measurements, and results are subject to interpretation or only provide binary output (retraction/no-retraction). Currently, there are no commercial instruments or assays that can quantitatively measure clot retraction. Platelets are crucial to prevent excessive bleeding following traumatic injury,5 the leading cause of preventable combat deaths. Platelet transfusions significantly improve the hemostatic outcome in actively bleeding patients. The manufacture and storage of platelet products for transfusion leads to a decline in platelet function. There is no effective test for platelets in the bag providing proof of function to serve as quality control of the platelet product. Platelet yield and pH are currently the only required quality control tests for stored platelet products, but they may not provide sufficient information about platelet quality and function. This effort seeks to develop a device based on a method that can use low sample volume and high throughput to screen donors and platelet-containing products for dysfunction(s) for in vitro and in vivo platelet research, prior to product release to hospitals, for routine platelet quality control, and/or for clinical use in patients. This device will significantly impact military (anticipated use in Role of Care 2 and 3 settings) civilian blood banking and transfusion services. The need for rapid deployment of platelets in hemorrhage scenarios has continued to spur development of new techniques, media, storage bags, and transport containers to enhance and extend platelet shelf-life, and a definitive, clinically relevant measurement of platelet functional viability will provide the metrics required to determine the impact of these advances, aligning with the US Air Force medical service ICD for blood-like products, technology, and documents of joint hemorrhage control. The goal of this topic is to develop a novel handheld device that measures clot retraction dynamics, provides portability and ease of use, facilitates rapid decision-making, integrates with existing systems (e.g. interfacing with electronic medical records (EMRs) or clinical decision support systems), and supports a wide range of applications (e.g. routine clinical diagnostics, point-of-care testing, and plate biology research environments). If the technology is fielded for military use, it may require additional security measures such as cybersecurity for data protection. PHASE I: Phase I will consist of designing schematics and diagrams resulting in the development of a proof-of-concept prototype that will form the basis for a portable, handheld, device that can characterize platelet contractility (AKA clot retraction ) from a blood or platelet-rich plasma sample as a definitive measurement of the platelets' functional viability. Limited, benchtop testing of the technology should be provided to assess accuracy, reproducibility, and reliability in measuring clot contractility parameters. Performer will conceptualize a method to quantitatively measure the platelet capacity for clot retraction and determine the technical feasibility to miniaturize the technology for handheld usage. It is expected that Phase I will result in clear methodology for the approach, demonstration of feasibility for miniaturization, sensor technology, and data processing. A detailed plan for further development, including regulatory approval pathways and commercialization strategies, should be provided. PHASE II: Phase II will focus on production and optimization of prototype hardware from Phase I. Emphasis on device design optimization for field and clinical use, including robustness, power supply, speed of results ( 30 min from start of test to results desired), weight, throughput and user interface should be included. Preclinical studies should be conducted by the end of Phase II that demonstrate validated performance of the fabricated device using human blood platelets. Validation of device output metrics should be conducted in comparison or correlation with accepted clinical and/or laboratory-based assays. The key performance parameter is reporting the output metric(s) of the platelet contractility ( clot retraction ) measurement. The values associated with (preliminary) expected normal ranges for these metrics for a healthy adult (free of antiplatelet medication) are required. Output from the device should be capable of quantifying the function and viability of the platelets to the user based on these normal ranges. Required Phase II deliverables will include: 1) successful refinement of a prototype product, 2) successful evaluation of the efficacy of the product, and 3) delivery of no less than 3 prototypes that provide data demonstrating outcomes. For this phase, the applicant will include the FDA regulatory path, which will provide a clear plan on how FDA clearance will be obtained if exemption is not applicable. It is also recommended that the applicant begin establishing relationships with commercialization partners to facilitate transition of the technology. PHASE III DUAL USE APPLICATIONS: This Phase III effort should result in a device that is commercially viable in civilian clinics and militarily relevant by providing a solution to a known capability gap: measuring platelet function through clot contractility. The vision for this product is a lightweight, handheld device that will assay platelet functional viability and provide this data to the user in the context of a range of values defined as clinically normal . Phase III will consist of device design finalization, delivery of at least 3 devices for military testing, FDA-required testing (e.g. validation testing to aid in regulatory approval), as well as development of any related training and usage materials. Potential buyers for the commercialized product include DoD and civilian blood donor centers, as well as DoD and civilian clinical laboratories that conduct hematology work. The product generated should be assigned a national stock number (NSN) to be added to the Defense Logistics Agency's electronic catalog (ECAT), General Services Administration (GSA) Advantage, etc. for purchase by individual units using Government Credit Card or for enterprise-level purchase orders. The FDA may eventually direct usage of the device as it provides insight into the capability of the blood product to provide the desired function. REFERENCES: 1. Lipets EN, Ataullakhanov FI. Global assays of hemostasis in the diagnostics of hypercoagulation and evaluation of thrombosis risk. Thromb J. 2015;13(1):4. 2. Stratmann J, Karmal L, Zwinge B, Miesbach W. Platelet Aggregation Testing on a Routine Coagulation Analyzer: A Method Comparison Study. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2019;25:1076029619885184. 3. Nakahara H, Sarker T, Dean CL, Skukalek SL, Sniecinski RM, Cawley CM, et al. A Sticky Situation: Variable Agreement Between Platelet Function Tests Used to Assess Anti-platelet Therapy Response. Front Cardiovasc Med. 2022;9:899594. 4. Jansen EE, Hartmann M. Clot Retraction: Cellular Mechanisms and Inhibitors, Measuring Methods, and Clinical Implications. Biomedicines. 2021;9(8). 5. Hamada SR, Garrigue D, Nougue H, Meyer A, Boutonnet M, Meaudre E, et al. Impact of platelet transfusion on outcomes in trauma patients. Crit Care. 2022;26(1):49. KEYWORDS: Blood platelets, platelet activation, diagnostic techniques (medicine), clinical laboratory techniques (medicine), blood storage, blood transfusions, portable equipment, platelet function, platelet shelf-life, platelet contraction
