DOD SBIR 24.2 Annual

Active
No
Status
Open
Release Date
April 17th, 2024
Open Date
May 15th, 2024
Due Date(s)
June 12th, 2024
Close Date
June 12th, 2024
Topic No.
DHA242-003

Topic

Hydrogel-based Drug Delivery Product(s) for Traumatic Brain Injury

Agency

Department of DefenseN/A

Program

Type: SBIRPhase: BOTHYear: 2024

Summary

The Department of Defense (DOD) is seeking proposals for a hydrogel-based drug delivery product for traumatic brain injury (TBI). The objective is to develop a biodegradable hydrogel system that can seal open-skull fractures or penetrating TBIs and release hemostatic agents, antimicrobials, and drugs to prevent brain swelling and herniation. The product should be easily administered by combat medics and have the potential for self or buddy-administration in austere settings. The proposal should include proof-of-concept for a hydrogel-based drug delivery platform in Phase I and pre-clinical in vivo exploratory studies in Phase II. The performer should also develop a transition plan for operational capability and demonstrate the potential for civilian use. The performer's transition plan should include a clinical development plan, product development plan, and a business case for commercialization. The deadline for proposal submission is June 12, 2024. For more information, visit the DOD SBIR website.

Description

OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): Combat Casualty Care

 

OBJECTIVE: To develop and validate a biodegradable hydrogel drug delivery system for open-skull fracture or penetrating traumatic brain injury (TBI) designed to seal the wounded environment and facilitate the controlled, continuous release of hemostatic agents to stop intracerebral hemorrhage, antimicrobials to prevent infection, and drugs to prevent brain swelling and herniation.

 

DESCRIPTION: Traumatic brain injury (TBI) is a significant health issue affecting military service members during both wartime and peacetime. Care for TBI will be particularly challenging for military medics as it will extend over a prolonged period, in far-forward, austere settings. Yet, this prehospital phase of care is vitally important as the first link in the chain to prevent death and to limit secondary injuries for TBI combatants. Currently, no therapeutic intervention is available as neuroprotective treatment for TBI. In the battlefield, supportive measures usually include restoration of blood pressure and tissue oxygenation through resuscitation or control of intracranial hypertension with hypotonic saline. However, all these measures require skilled paramedics and reasonable medical settings, which are often not feasible during combat. Future improvement in combat casualty outcomes depends on closing the gap in prehospital care. One approach is to develop therapeutic products that can be readily available for administrating by a Combat Medic and/or self or buddy-administration to mitigate morbidity and mortality from TBI during prolonged field and enroute care.

 

Hydrogels are stable, highly malleable, and easily transportable matrixes that can potentially carry multiple therapeutics. They are easy to apply and offer a promising solution for the point-of-injury care for TBI. Moreover, they are ideal for extended release of drugs directly at the site of injury, bypassing the systemic route and thus limiting potential adverse effects (Fernandez-Serra, Gallego, Lozano, & Gonzalez-Nieto, 2020; Ma et al., 2020). The desired end-product would be a combination (biologic + drug) therapy product utilizing an FDA-approved biodegradable hydrogel combined with an FDA-approved drug that has demonstrated significant evidence of therapeutic benefit in the preclinical TBI literature. The product target should be for TBI patients presenting with skull fracture or penetrating wounds to the brain. This system should be designed to seal the wounded environment and facilitate the controlled, continuous release of individual or multiple therapeutics including antimicrobials to prevent infection, antioxidants, and anti-inflammatory drugs to prevent cellular damage, brain swelling, and herniation. The release of the drug(s) should be unidirectional, facilitating drug infusion into the injured tissue while mitigating any seepage into re-sutured skin and/or gauze bandages. A successful awardee will design, develop, and demonstrate the utility of a hydrogel-embedded drug formulation for TBI in pre-clinical studies.

 

PHASE I: Demonstrate the feasibility of the concept by providing proof-of -concept hydrogel-based drug delivery platform for TBI that has the potential to meet the broad needs discussed in this topic description. Currently there are no FDA-approved, field-capable materiel solutions that can be used for open-head wounds or penetrating brain injuries. The proposed studies should consider the ability of the hydrogel to provide the safe, controlled release of known neuroprotective drugs directly to the injured brain. Accompanying the application should be standard protocols and procedures for its use and integration into ongoing programs.

 

PHASE II: The Performer will validate the feasibility of the proposed product by completing pre-clinical in vivo exploratory studies in established small (i.e., rat) animal models of TBI to (1) demonstrate the safety of the hydrogel product, (2) validate pharmacokinetic and pharmacodynamics (PK/PD) properties of the hydrogel-embedded drug delivery approach, and (3) demonstrate therapeutic efficacy of the hydrogel-embedded drug(s) for TBI. PK/PD evaluation shall include selectivity, bioavailability, bio-distribution, half-life, stability, and clearance of the drugs in brain tissue and blood/plasma. Drug candidates of interest include, but are not exclusive to, dexamethasone, acetyl L-carnitine, glyceryl tri-acetate, resveratrol tri-acetate, cyclosporine, n-acetylcysteine, candesartan, and minocycline.

 

Phase II Deliverables

The Performer shall submit to DoD technical data and results of experiments demonstrating proof-of-concept and safety of candidate hydrogel + drug formulation(s) in defined small (i.e., rat) animalmodels of TBI non-GLP laboratory studies.
The Performer shall submit a Regulatory Development Plan to include identification of the formalregulatory pathway, records of any informal FDA communications guiding their recommendedpathway, referenced hydrogel 510K device already FDA cleared/approved, novel combination withdrug Target Product Profile (TPP) and/or Indication for Use (IFU), projected FDA meeting types, andtop three risks or questions proposed to settle with FDA interactions. The Performer shall provideevidence of FDA interactions confirming whether the novel combination of previously FDA clearedhydrogel + drug may or may not require additional Phase 1 safety studies and/or additional pre-clinicalstudies required by the Agency prior to further clinical development.

 

PHASE III DUAL USE APPLICATIONS: The Performer shall focus on transitioning the technology from pre-clinical research, through FDA regulated trials, to operational capability and should demonstrate that this system could be used in a broad range of military and civilian medical facilities including by Combat Medics or by buddy administration in austere medical environments. The Performer shall develop a Transition Plan to demonstrate their strategy to infiltrate civilian markets and align to a military operational requirement. The Performer shall discuss technical risks of the approach, costs, benefits, and plan for further development. The Performer shall interface with the U.S. Army Acquisition Medical Research and Development Command (MRDC) Advanced Development Team early to ensure the product aligns to military-relevant use requirements outlined in the current Concepts of Operations. Performers shall integrate the criteria for transitioning to Advanced Development and into the plan. The Performer’s Transition Plan shall also demonstrate need for the product by civilian sector stakeholders. Performer shall conduct analysis for commercial viability, via market research data, for possible use in prehospital setting, to include first responders, paramedics, and ambulance transport, and hospital settings. Phase III will require a detailed plan to test the hydrogel + drug product developed in Phase I-II in a larger animal model (pigs, dogs, macaques, etc.), as well as human studies. All research involving animals shall comply with the applicable federal and state laws and agency policy/guidelines for animal protection. Considerations should include material and process documentation, and verifiable data sets on animal samples. The detailed plan shall cite the FDA interactions from Deliverables in Phase II and discuss the steps required for transition from pilot lots of prototypes towards manufacturing process amenable to (cGMP-compliant) pilot lot production. GLP safety and toxicity studies in animal model systems, studies to evaluate the pharmacokinetics and pharmacodynamics (PK/PD), and study specifics for stability and shelf-life studies shall also be discussed in the plan.

 

The Performer’s transition plan shall propose a Clinical Development Plan for FDA regulated Phase 2 and 3 clinical trials to include optimal dosing concentration and regimen determination demonstrated via PK/PD studies, clinical trial synopsis, targeted TBI population, power analysis, and primary outcome measure for efficacy.

 

The Performer’s transition plan shall discuss Product Development Plan to include manufacturing readiness to support Phase 2 and 3 clinical trials, drug packaging and distribution partnerships, results of release and stability studies completed, and a plan for scaling to GMP certified manufacturing partners if not already established.

 

Lastly, the Performer’s transition plan shall discuss the business case to include commercial partner alliance(s), intellectual property protections, patent status, any licensing agreements and plans for commercialization. Private industry can be sought for production of using Good Manufacturing Practice (GMP) processes, either by the small business or under license. Ideally, the Performer will be the regulatory sponsor for clinical studies necessary to demonstrate selective, targeted delivery to the brain, as well as clinical safety and efficacy. The Performer is encouraged to submit proposals to competitive applications to acquire and leverage additional funding sources (i.e. Congressional Directed Medical Research Program/CDMRP, Joint Warfighter Brain Health (JWBH), Combat Casualty Care Research Program (CCCRP), Medical Technology Enterprise Consortium (MTEC) and/or private investiture) adequate to support all development activities and ensure commercial availability and sustainability for the developed product(s).

 

REFERENCES:

Fernandez-Serra, R., Gallego, R., Lozano, P., & Gonzalez-Nieto, D. (2020). Hydrogels for neuroprotection and functional rewiring: a new era for brain engineering. Neural Regen Res, 15(5), 783-789. doi:10.4103/1673-5374.268891 
Ma, X., Agas, A., Siddiqui, Z., Kim, K., Iglesias-Montoro, P., Kalluru, J., . . . Haorah, J. (2020). Angiogenic peptide hydrogels for treatment of traumatic brain injury. Bioact Mater, 5(1), 124-132. doi:10.1016/j.bioactmat.2020.01.005

 

KEYWORDS: Hydrogel, traumatic brain injury, penetrating brain injury, extended drug release, TBI, skull fracture

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