TECHNOLOGY AREA(S): Biomedical
OBJECTIVE: A capability is sought to ensure off-the-shelf, large volumes of stockpiled cell and tissue biologics that would be in high demand following a mass casualty event in military theaters of operation, in humanitarian response operations, or events on the homeland.
DESCRIPTION: Mass casualty events place enormous logistical strain on medical infrastructure, overwhelming personnel and rapidly depleting available medical supplies. This necessitates the stockpiling of medical supplies and therapeutics for on-demand use in the event of a healthcare surge. Tissue transplantation and regenerative medicine hold tremendous potential to treat injuries common in mass casualty events, but limited capabilities for storage and transportation of many biological materials severely constrains their application to this area of public health need. On and off the battlefield, mass casualty events involving radiation exposure, chemical or biological agents, and explosive or incendiary devices can create a diverse range of injuries requiring both urgent and continuing care. Events involving explosive devices, incendiary devices, and exposure to radioactive materials frequently result in thermal burns , while blistering agents such as sulfur mustard can cause severe chemical burns requiring treatment by skin grafting. Exposure to radiation levels far exceeding 2 Gray (Gy) resulting from detonation of a nuclear device or exposure to radioactive materials in the environment typically causes Acute Radiation Syndrome, the severity of which depends on the dose of radiation. Exposure to doses as low as 2 Gy causes moderate to severe bone marrow damage and is life-threatening, while exposure to higher doses can result in neutropenia, thrombocytopenia, severe gastrointestinal damage, hematopoietic syndrome, multi-organ failure, and other symptoms, necessitating a range of treatments including cytokine therapy, blood transfusion, stem cell therapy, bone marrow transplant, and prophylactic antibiotics . Explosive blasts commonly cause injury to major blood vessels in the extremities, requiring ligation, reconstruction, or grafting of a replacement vessel. Many injuries common in mass casualty events are amenable to tissue transplant and regenerative medicine treatments. A range of conditions caused by Acute Radiation Syndrome including hematopoietic syndrome, cytopenia, and direct damage to bone marrow  necessitate hematopoietic stem cell transfusion or bone marrow transplantation . Severe thermal burns and chemical burns can be treated by skin grafting. Severe burns over more than 20% total body surface area preclude the use of skin autograft, as the need for transplant skin is greater than can be supplied by the unaffected area, but cadaveric skin can be used either as a temporary antimicrobial wound dressing or (under narrow circumstances) as a permanent transplant. And arterial damage caused by blast injuries, particularly to the extremities, often requires treatment involving grafting of a new blood vessel. Although some disagreement exists over the preference for blood vessel auto- or allografts, in many trauma cases a venous autograft is not feasible, necessitating the use of a blood vessel from a cadaveric donor. The tissues required for these treatments are subject to significant storage constraints that are exacerbated during mass casualty events. Cadaveric skin that is cryopreserved using glycerol or dimethyl sulfoxide can currently be used as a temporary wound dressing with many clinical benefits, but the loss of cell viability resulting from current cryopreservation methods prevents its use as a current skin transplant. Refrigerated cadaveric skin can be used for permanent transplantation but it expires within weeks precluding disease testing and preventing its banking for mass casualty events. Bioengineered skin substitutes can be used for permanent grafting, but the same post-thaw viability limitations prevent their stockpiling for use as a medical countermeasure during a mass casualty event. Allogeneic bone marrow transplantation and hematopoietic stem cell transfusion are achievable after long-term storage, creating the potential for stockpiling of these biologics for use during healthcare surges. Current methods relying on cryopreservation in dimethyl sulfoxide are associated with a large range of adverse events in patients that receive these treatments including hypotension, dyspnea, cardiac arrhythmia, and in some cases cardiac or respiratory arrest, transient blood vessel occlusion, neurotoxicity, and renal failure, with increased susceptibility in children. Post-thaw washout of dimethyl sulfoxide can reduce toxicity but causes significant cell loss and cell damage, reducing clinical efficacy. Thus non-toxic cryoprotectant solutions are needed that can enable safe and simple post-thaw protocols for bone marrow and stem cell treatments. Moreover, new methods allowing for storage at higher temperatures (-80C or above) would enable rapid, cost-effective deployment from stockpiles to sites of mass casualty events. Current storage capabilities limit the efficacy of blood vessel banking. Cryopreservation, the only solution currently available for long-term storage, results in loss of endothelial viability, contributing to graft failure, thrombosis, and aneurysmal degeneration . Traditional freezing and thawing methods lead to fracturing of the vessel wall, limiting treatment efficacy. Some studies have reported impaired blood vessel functionality after cryopreservation, including smooth muscle contractility and collagen synthesis. Alternatives to traditional slow-freezing methods such as vitrification have shown potential to improve both the efficacy and the cost-effectiveness of banking transplantable vascular tissues . Improvements over the current state of the art can lead to effective stockpiling of cadaveric blood vessels for mass trauma injury, as well as a large number of other clinical applications. Capabilities for effective stockpiling of skin, blood vessels, bone marrow and marrow-derived stem cells will enable rapid and flexible responses to mass casualty events, with many other high-value military and civilian applications. This topic seeks the development novel methods to bank biologics for use in mass casualty events. Preservation methods for indefinite storage of transplantable tissues or tissue substitutes for treatment of trauma, burns, and radiation injury are encouraged, although other proposals for mass casualty applications will be considered as well.
PHASE I: The performer will develop the capability to successfully store harvested or engineered tissues that are typically in high demand following a mass casualty event for extended periods, with demonstration of efficacy as medical countermeasure following in-vivo use. Examples include the development of methods to allow for the long-term storage of full thickness skin or blood vessels or less/non-toxic ways to stockpile bone marrow. Proof of principle in vitro demonstration of post-preservation cell/tissue survival and tissue-specific functionality is required. Demonstration of short preservation times are acceptable if indicative of the potential success under longer preservation durations. Preservation approaches minimizing potential for toxicity to cell/tissue recipients are required. Evaluation and testing on tissue derived from commercially available animal or human tissue donor or on commercial tissue-based engineered products should use sources that do not require new or separate review by an institutional review board due to time constrains during Phase I. In addition, preliminary evaluation and testing of non-traditional tissue harvesting methods (e.g. harvesting bone marrow from living and potentially even recently deceased donors) are encouraged using only model systems that do not require review by animal use or human protection offices. Also required in Phase I is a description of the Food and Drug Administration (FDA) regulatory requirements for the proposed approach along with a regulatory development strategy. The focus of this phase is on developing preservative formulations or protocols that are suitable for use in Phase II.
PHASE II: The performer will demonstrate in an animal model the effectiveness of the storage formulations or protocols from in Phase I. The approaches developed should clearly demonstrate the ability to store the tissues under preservation conditions of biological inactivity and to return the preserved cells/tissue to a functional state post-preservation, for instance by successfully storing viable full thickness skin, large blood vessels and large volumes of bone marrow. The method developed should show no or minimal toxicity to cell/tissue recipients. Approaches conceived for field use under triage situations are encouraged but not required. Demonstration of functionality and/or therapeutic efficacy (in cases of tissue engineering constructs) post-preservation and following transplantation/treatment should be appropriate to the tissue and to the animal model selected.
PHASE III DUAL USE APPLICATIONS: Long term functional storage of complex biological tissue is a limiting capability for stockpiling of tissue biologics in case of mass casualty events in military theaters of operation, in humanitarian response operations, or events in the homeland. Beyond this, a large potential market exists for preservation technologies that can extend the storage of functional tissues and cells ex vivo for months and years. Progress in developing methods for long term preservation able to provide a long shelf life to engineered and natural complex cell/tissue therapies can transform current wound healing, regenerative medicine and cell therapy industries. The proposal must include a description of plans for the commercialization of the underlying technology. It is envisioned that the performer or a suitable partner will pursue development of the approach to permit the long term stockpiling and shelf-life. This award mechanism will bridge the gap between laboratory-scale innovation and entry into a recognized FDA regulatory pathway leading to commercialization.
- "Explosions and Blast Injuries: A Primer for Physicians." Centers for Disease Control. Http://www.cdc.gov/masstrauma/preparedness/primer.pdf Accessed May 2015.
- Waselenko, J.K. et al. "Medical Management of the Acute Radiation Syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group" (2004). Annals of Internal Medicine. 140(12):1037-51.
- Weisdorf, D. et al. "Acute Radiation Injury: Contingency Planning for Triage, Supportive Care, and Transplantation" (2006). Biology of Blood and Marrow Transplantation. 12(6):672-682.
- Randon, C. "Fifteen years of infrapopliteal arterial reconstructions with cryopreserved venous allografts for limb salvage" (2010). Journal of Vascular Surgery. 51:869-77.
- Brockbank, K.G.M. “Vitrification of Heart Valve Tissues” (2015). Cryopreservation and Freeze-Drying Protocols. 1257:399-421.
KEYWORDS: Disaster, response, mass, casualty, biologics, preparedness, tissue, engineering
- TPOC-1: Lt. Col. Luis Alvarez
- Phone: 512-699-5281
- Email: email@example.com