OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): Biotechnology OBJECTIVE: Develop a portable, automated, closed-loop system for delivering oxygen (O2) directly to the bloodstream via an intravascular catheter and maintaining a selected level of blood O2 saturation. DESCRIPTION: Combat casualties can result in acute lung injury (ALI), which can progressively worsen to acute respiratory distress syndrome (ARDS) within 6 to 72 hours after initial injury (Diamond et al., 2023). In combat trauma patients, the incidence and prevalence of ARDS has been found to range from 3%-33%, with mortality rates between 13% and 33% (Broderick et al., 2022). Increased mortality rates of up to 56% have been observed in cases of blast lung injury (BLI), a known antecedent of ARDS (Broderick et al., 2022). With the increased prevalence of enhanced blast weapons such as thermobaric explosives in modern warfare, it is expected that prevalence of BLI and resulting ARDS will increase further. In cases of ARDS, respiratory distress escalates following initial lung injury over the course of several hours to several days, during which difficulty in breathing ultimately leads to dangerously low levels of O2 in the blood (hypoxemia) and, if left untreated, hypoxia-induced tissue damage throughout the body (Diamond et al., 2023). With a shift toward Special Operations Forces missions in remote, austere locations, rather than in defined theaters of operations, access to definitive medical care may not be available for days (Keenan and Riesberg, 2017). Moreover, while the air, ground, and sea dominance of US Forces during the Global War on Terror in Afghanistan and Iraq offered ample opportunity for medical evacuation to clinical care facilities, such ease of mobility and evacuation capabilities are not the case for conflicts with near-peer adversaries i.e., adversarial nations with equivalent military capabilities (Epstein et al., 2023). Together, these characteristics of modern warfare highlight the need for advances in prolonged field care for situations in which evacuation of critically injured military personnel may be delayed or infeasible. Current approaches to treating ARDS require highly trained medical personnel in a clinical setting. Most commonly, treatment involves intubation and mechanical ventilation, during which the patient must be deeply sedated to tolerate the endotracheal tube. In some cases, mechanical ventilation can further exacerbate lung damage in the context of ARDS (Diamond et al., 2023). If ARDS progresses and oxygenation cannot be adequately accomplished via mechanical ventilation, venovenous extracorporeal membrane oxygenation (VV ECMO) can be initiated as a rescue therapy. While VV ECMO has been used to successfully deliver oxygenated blood to patients with severe respiratory failure, this approach requires a highly trained team of clinicians to administer and continuously monitor. Blood-surface interactions associated with VV ECMO pose medical risks such as thrombosis, hemorrhage, and infection, decreasing the benefit to risk ratio for this approach. Many of the risks of VV ECMO could be mitigated by an approach that does not require blood to be treated extracorporeally but could instead deliver O2directly to the bloodstream intravascularly. One such approach was accomplished by the IVOX device, which, in a human clinical trial, delivered O2 directly to blood within the vena cava via passive O2 transfer through follow fibers composed of a gas permeable membrane (Conrad et al., 1994). While the IVOX device was able to deliver 40-70 mL O2 to the blood per minute, reducing the degree of mechanical ventilation required, complications arising from the large insertional diameter of the catheter (12-16 mm), including bleeding during insertion or explantation, venous thrombosis, and vascular obstruction, as well as mechanical and performance malfunction issues with the device, prohibited subsequent regulatory approval for clinical use. Recent development of nonporous amorphous fluoropolymer hollow fiber membranes that generate a large driving concentration gradient for O2 diffusion provide an enabling technology for delivering equivalent O2 concentrations across a smaller surface area as compared to the IVOX catheter, facilitating the development of smaller-diameter catheters with greater ease of insertion and a reduced risk of complications associated with insertion and removal of the device (Farling et al., 2020; Straube et al., 2022). Pairing such technology with advances in closed-loop monitoring of patient state and responsive intervention could revolutionize prolonged field care approaches for U.S. military missions with limited availability of medically trained personnel. A portable, automated system for safe monitoring and delivery of O2 directly to the bloodstream would support timely treatment of wounded warfighters on the battlefield, reducing mortality rates as well as downstream clinical complications resulting from ALI and ARDS. PHASE I: This topic solicits Direct to Phase II (DP2) proposals only. Proposers must provide data demonstrating that the following has been achieved outside of the SBIR program: development and benchtop validation of a research-grade intravascular oxygenation catheter with a diameter no larger than 32 Fr (1.07 cm), intended for venous insertion, that can deliver O2 directly to blood at a rate of 50 ml/min. Proposers interested in submitting a DP2 proposal must provide documentation to substantiate that the scientific and technical merit and feasibility described above has been met and describe the potential commercial applications. Documentation should include, reference, or summarize all relevant information including, but not limited to technical reports, test data, prototype designs/models, and performance goals/results. PHASE II: DARPA is interested in novel approaches to develop a breadboard system that can integrate with prototype intravascular oxygenation catheters to automatically deliver O2 directly to a patient's bloodstream following catheter insertion. The proposed integrated breadboard system must include a portable control device designed to directly interface with an O2 canister, at least two intravascular oxygenation catheters, and one or more devices that can monitor ongoing changes in blood O2 saturation level. Moreover, the system must include a user interface for clinician input of target O2 saturation level and thresholds for system alarms, as well as a real-time display of blood O2 saturation level. Proposers must also describe plans for development and validation of algorithms enabling closed-loop auto-titration of blood O2 saturation level, as well as integration of these algorithms into the proposed system, such that continuous manual intervention would not be required to maintain desired blood oxygenation parameters following catheter insertion and initial input of system settings. Proposers must specify whether the device will enable independent closed-loop auto-titration settings for each integrated catheter. Proposers must also specify safety parameters that will be implemented in the integrated system. As DARPA ultimately envisions a system intended for use in prolonged field care scenarios, proposers must describe the planned size, weight, and power (SWAP) specifications for the breadboard system. It is anticipated that further miniaturization for brassboard system development may occur beyond the scope of this SBIR. Proposals must also describe planned research and development efforts to increase O2 transfer efficacy of existing research-grade intravascular oxygenation catheters by designing, developing, and validating a small-diameter catheter intended for insertion in a human femoral vein. The catheter must have a diameter no larger than 25 Fr (0.83 cm) and must be demonstrated in a benchtop setting to directly transfer O2 to blood at a rate of 50 ml/min. Proposers must describe efforts to quantify both O2 transfer rate, as well as carbon dioxide (CO2) removal rate, that can be achieved by the catheter. Proposers must clearly describe the design of all proposed benchtop validation systems, as well as their relevance to clinically relevant scenarios, such as similarity to human intravascular blood flow, as well as changes in blood oxygenation levels due to cellular uptake of O2 from blood or to potentially worsening intrinsic lung function due to secondary damage following traumatic injury. Proposers may choose to utilize existing benchtop hardware and approaches for validation of breadboard system functionality, or, alternatively, respondents may propose the development of iterative or new validation approaches as part of their proposal. The interim and end-phase goals for the base period are as follows. Responders to this topic are strongly encouraged to propose additional interim assessments to further demonstrate progress toward the goals specified below. Month 6: o Initial feasibility and design of small-diameter intravascular oxygenation catheter with insertion diameter < 25 Fr. o Initial feasibility and design of breadboard system for closed-loop, auto titration of O2 saturation. o Finalization of benchtop validation system(s) that can be used to test functionality of closed-loop O2 titration system and small-diameter intravascular oxygenation catheter. Month 12: o Benchtop demonstration of closed-loop, auto titration capability of breadboard system for O2 delivery using a previously developed prototype intravascular catheter. o Benchtop demonstration of O2 delivery at a rate of > 50 mL/min via prototype small-diameter intravascular oxygenation catheter with insertion diameter 25 Fr. o Characterization of CO2 removal from prototype small-diameter catheter. o Benchtop demonstration of closed-loop, auto titration capability of integrated breadboard system with two catheters (one of which may be no larger than 25 Fr) to deliver O2 directly to blood at a rate of 50 ml/min per catheter and to maintain an O2 saturation level of at least 88%, for a duration of at least 3h in a single session and for at least 50h over the course of multiple test cycles. Option Period 1: Proposals that respond to Option Period 1 may also include a sequential 6-month option period for a pre-clinical pilot study to demonstrate and validate the functionality of their integrated breadboard system and small-diameter catheter in a large animal model. Month 18: o Assess capability of fully integrated, closed-loop breadboard system to deliver O2 directly to blood via an intravascular oxygenation catheter and to maintain a defined level of O2 saturation. o Demonstrate insertion of small-diameter catheter in the femoral vein of a large animal model and assess O2 transfer rate. Schedule/Milestones/Deliverables. Phase II fixed payable milestones for this program include: Base Period: o Month 1: Phase II Kickoff briefing (with annotated slides) to the DARPA Program Manager (PM) including: any updates to the proposed plan and technical approach, risks/mitigations, schedule (inclusive of dependencies) with planned capability milestones and deliverables, proposed metrics, and plan for demonstration and validation of breadboard system and prototype catheter. o Month 3: Report on progress toward benchtop validation system development and design of small-diameter intravascular oxygenation catheter and closed-loop system for auto titration of O2 saturation. o Month 6: Report on development of small-diameter intravascular oxygenation catheter and closed-loop system for auto titration of O2 saturation. o Month 9: Report on development of small-diameter intravascular oxygenation catheter and closed-loop system for auto titration of O2 saturation and progress toward breadboard closed-loop system o Month 12: Report on benchtop demonstration of system component functionality, including (1) closed-loop, auto-titration capability of breadboard system, (2) characterization of O2 delivery rate from prototype small-diameter intravascular oxygenation catheter, (3) characterization of CO2 removal from prototype small-diameter catheter, and (4) benchtop demonstration of integrated breadboard system. Option Period: o Month 13: Submission of animal use protocols for review by an Institutional Animal Care and Use Committee (IACUC) and the US Army Medical Research & Development Command (USAMRDC) Animal Care and Use Review Office (ACURO). o Month 15: Report on progress toward assessment of integrated breadboard system and small diameter catheter in large animal model. o Month 18: Report on demonstration of integrated breadboard system and small diameter catheter in large animal model. PHASE III DUAL USE APPLICATIONS: This SBIR has potential applicability across DoD and commercial entities. For DoD, both a portable system for closed-loop O2 delivery and auto titration of O2 saturation, as well as a small-diameter intravascular oxygenation catheter, will provide new capabilities for treatment of acute lung injury in wounded military personnel, particularly in prolonged field care settings with limited availability of medically trained personnel and specialized medical equipment. In the commercial sector, the same technologies have applicability for treating wounded individuals in remote settings in which transport to a hospital is difficult or infeasible. REFERENCES: 1. [1] Broderick JC, Mancha F, Long BJ, et al. (2022). Combat trauma-related acute respiratory distress syndrome: a scoping review. Critical Care Explorations 4(9):e0759. doi: 10.1097/CCE.0000000000000759. 2. [2] Epstein A, Lim R, Johannigman J, et al. (2023). Putting medical boots on the ground: lessons from the war in Ukraine and applications for future conflict with near-peer adversaries. Journal of the American College of Surgeons 237(2): 364-373. doi:10.1097/XCS.0000000000000707 3. [3] Conrad SA, Bagley A, Bagley B, and Schaap RN. (2004). Major findings from the clinical trials of the intravascular oxygenator. Artificial Organs 18(11): 846-63. doi: 10.1111/j.1525-1594.1994.tb03334.x Available from: https://pubmed.ncbi.nlm.nih.gov/7864735/ 4. [4] Diamond M, Peniston HL, Sanghavi DK, et al. Acute Respiratory Distress Syndrome. [Updated 2023 Apr 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK436002/ 5. [5] Keenan S and Riesberg JC. (2017). Prolonged field care: beyond the golden hour. Wilderness & Environmental Medicine 28: s135-9. doi: 10.1016/j.wem.2017.02.001 6. [6] Straube TL, Farling S, Deshusses MA, et al. (2022). Intravascular gas exchange: physiology, literature review, and current efforts. Respiratory Care 67(4): 480-493. doi: 10.4187/respcare.09288 KEYWORDS: acute lung injury, acute respiratory distress syndrome, blood oxygenation, catheter
