What are possible U.S. Department of Defense (DoD) applications for chondroitin sulfate glycosaminoglycan (CS-GAG) hydrogels?

The Homeland Defense and Security Information Analysis Center recently conducted research and analysis on possible DoD applications for CS-GAG hydrogels.

Background

CS-GAG hydrogels are a modification of hyaluronic acid (HA). HA, found naturally in the human body, is produced in the plasma membrane of vertebrate cells [1]. HA hydrogels have been used successfully in cell delivery and many other biomedical applications [2]. Modification of natural HA to create CS-GAG hydrogels includes chemically adding additional sulfate groups to enhance their durability within the body [3]. Commonly used in cell delivery or transplant applications, hydrogels are successful because they have properties similar to surrounding tissue, which prevents rejection by the body [3]. The CS-GAG hydrogels create a matrix that encapsulates target cells to transplant into the body [3].

Traumatic Brain Injury

Understanding the interdependencies among different neurological disorders bridges the gap between research and treatment. Traumatic brain injury is a neurological disorder closely correlated with post-traumatic stress disorder [4]. According to a study funded by the U.S. Office of Veterans Affairs, at least 20 percent of Iraq and Afghanistan veterans suffer from PTSD. The number more than doubles, however, when TBI is considered [5]. Addressing and treating neurological damage can help promote the treatment of psychological disorders [6]. HDIAC identified the benefits of using CSGAG hydrogels to repair neurological damage after TBI so that it may help alleviate PTSD.

CS-GAG hydrogels have neural stem cells integrated in the matrix for treating TBI [3]. There is an increase in the incidence of TBI among active-duty U.S. military personnel due to heavy use of improvised explosive devices.

HDIAC identified a capability gap and recommended solutions and further uses for CS-GAG hydrogels. Statistics show 92 percent of TBI incidents are mild to moderate. Severe TBI, the target demographic for treatment with CS-GAG hydrogel, is approximately 8 percent of total cases [7].

Research indicates treatment gaps in mild TBI cases, which are the most common. By focusing on the use of CS-GAG hydrogel in the most severe occurrences, researchers eliminate 92 percent of potential patients [8]. The CS-GAG hydrogels have innovative properties that prevent their degradation by enzymes, allowing them to remain in the body and extend the time stem cells have to generate and grow [3]. In addition, CS-GAG hydrogels have anti-inflammatory factors, so they are safe to use in the brain and do not cause additional swelling [3].

Vision

HDIAC’s analyses included DoD applications that will benefit servicemen as well as civilians. There is a neurological connection between the eye and the brain, thus TBI may affect vision [9]. Among service members who served in Operations Enduring Freedom and Iraqi Freedom, eye trauma is the second most common injury and 75 percent of TBI patients experience vision problems [10]. Hyaluronic acid is a natural wound healer and is found as a component of eye tissue [11]. Traditionally, drug carriers have not been successful in the eye because they are unable to maintain localized sustained release of drugs [12]. CS-GAG hydrogel degrades at a slower rate than HA hydrogels, and thus, is a better solution for drug delivery to the eye.

Hearing

HDIAC highlighted some additional areas of research where CS-GAG hydrogels would greatly benefit and extend current research. Hearing impairment is the most common form of service-connected disability among military veterans and one of the more common sensory losses resulting from blast trauma [13, 14]. The inner ear hair cells transform sounds into electrical signals, which are sent to the brain for interpretation. Damage to these cells by loud noises, as would be common on the battlefield, can cause hearing impairment or even deafness [14]. HDAIC made the connection between the similarities of the inner ear hair cells and neural stem cells. Inner ear hair cells are non-regenerative, but neural stem cells have similar characteristics and are able to reestablish some auditory contacts, making them a potential replacement [14].

Developing effective inner ear hair cells from neural stem cells is difficult due to the nervous integration of these cells [14]. The hydrogel’s ability to enhance trophic factors, molecules that allow a neuron to develop and maintain connections [15], could be beneficial in overcoming this obstacle.

Knee Injury

HDIAC recognized that rigorous physical training associated with the U.S. Army, and in-the-field complications, makes knee injuries among the most common musculoskeletal injuries in the Army, and connected these statistics to the research done with CS-GAG hydrogels [16]. Normal wear and tear of knee cartilage cause pain and loss of functionality and tissue engineering can be employed as a potential treatment. Tissue engineering mainly focuses on developing tissue and organ substitutes [17]. Clinical methods are limited in their cartilage tissue regeneration, thus tissue regeneration with Sulfated CS-GAG can be a viable solution. Hydrogels alone lack the robustness required for many applications [18] but Sulfated CS-GAG in conjunction with growth factors can be used as a matrix to promote cartilage regeneration, a challenge not yet achieved [19].

Conclusion

The need for biomimetic research, like that of CS-GAG hydrogels, will continue to prove themselves multifunctional. Longitudinal studies and trend analysis will determine future growth in this field. The research completed by HDIAC highlighted the value of CS-GAG hydrogels on future DoD applications.

References

1. Fraser, J. R., Laurent, T. C., & Laurent, U. B. (1997). Hyaluronan: Its nature, distribution, functions, and turnover. Journal of Internal Medicine, 242(1), 27-33. doi:10.1046/j.1365- 2796.1997.00170.x

2. Burdick, J. A., & Prestwich, G. D. (2011). Hyaluronic Acid Hydrogels for Biomedical Applications. Adv. Mater., 23(12). doi:10.1002/adma.201003963

3. Karumbaiah, L., Enam, S. F., Brown, A. C., Saxena, T., Betancur, M. I., Barker, T. H., & Bellamkonda, R. V. (2015). Chondroitin Sulfate Glycosaminoglycan Hydrogels Create Endogenous Niches for Neural Stem Cells. Bioconjugate Chem. 26(12), 2336-2349. doi:10.1021/acs.bioconjchem.5b00397

4. Lash, M. (2015) TBI and PTSD: Navigating the Perfect Storm. Retrieved from http://www.brainlinemilitary.org/content/2013/03/tbi-and-ptsdnavigating-the-perfect-storm_pageall.html (accessed January 26, 2016).

5. Veterans Statistics: PTSD, Depression, TBI, Suicide. (2015, Sept. 20). Veterans and PTSD. Retrieved from http://www.veteransandptsd.com/PTSD-statistics.html (accessed January 26, 2016).

6. Schwarzbold, M., et al. (2008). Neuropsychiatric Disease and Treatment, 4(4): 797-816. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536546/ (accessed January 26, 2016).

7. DoD Numbers for Traumatic Brain Injury Worldwide – Totals. (2015) Defense and Veterans Brain Injury Center. Retrieved from http://dvbic.dcoe.mil/sites/default/files/Worldwide-Totals-2015.pdf (accessed January 26, 2016).

8. French, L. M. (2010). Military Traumatic Brain Injury: An Examination of Important Differences. Brainline Military. Retrieved from http://www.brainlinemilitary.org/content/2011/01/military-traumatic-brain-injury-an-examination-of-important-differences_pageall.html (accessed January 26, 2016).

9. Cooper, L. (2015, May 1). Reference Card Helps Identify TBI-related Vision Problems. Retrieved from http://www.health.mil/News/Articles/2015/05/01/Reference-Card-Helps-Identify-BIrelated-Vision-Problems (accessed January 26, 2016).

10. Military Health System Communication Office. (2014, March 11). Eye Injury Registry Promises to Advance Vision Care. Retrieved from http://www.health.mil/News/Articles/2014/03/11/Eye-Injury-Registry-Promises-to-Advance-Vision-Care (accessed January 26, 2016).

11. Wirostko, B., Mann, B. K., Williams, D. L., & Prestwich, G. D. (2014). Ophthalmic Uses of a Thiol-Modified Hyaluronan-Based Hydrogel. Advances in Wound Care, 3(11), 708-716. doi:10.1089/wound.2014.0572

12. Widjaja, L., Bora, M., Chan, P., Lipik, V., Wong, T., & Venkatraman, S. (2013). Hyaluronic acid-based nanocomposite hydrogels for ocular drug delivery applications. J. Biomed. Mater. Res., 102(9), 3056-3065. doi:10.1002/jbm.a.34976

13. Severe Hearing Impairment Among Military Veterans — United States, 2010. (2011, July 27). Morbidity and Mortality Weekly Report, 60(28): pgs 955-958. Retrieved from http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6028a4.htm (accessed January 26, 2016).

14. Christopherson, G. T., & Nesti, L. J. (2011, October 19). Stem cell applications in military medicine. Stem Cell Research and Therapy, 2(5). Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308037/ (accessed January 26, 2016).

15. Trophic Factors. (2015). ALS Association. Retrieved from http://www.alsa.org/research/about-als-research/trophic-factors.html?referrer=https://www.google.com/ (accessed January 26, 2016).

16. Patnaik, P., Amoroso, P., Mundt, K., & Bigelo, C. (2000). Disabling Knee Injury in the United States Army: Classification of Injury for Etiological Research. Military Performance Division. U.S. Army Research Institute of Environmental Medicine. Retrieved from https://www.google.com/url?sa=t&rct=-j&q=&esrc=s&source=web&cd=4&cad=rja&uact=8&ved=0CDY Q F j A D a h U K E w j M n d _C 7 u D I A h W K R y Y K H W 0 I B -wU&url=http%3A%2F%2Fwww.dtic.mil%2Fcgi-bin%2FGetTRDoc%-3FAD%3DADA 383861%26Location%3DU2%26doc%3DGetTRDoc.pdf&usg=AFQjCNFELEuJS2Slg1qXe1mMcRaR2gzQeA (accessed January 26, 2016).

17. Castells-Sala, C., Alemany-Ribes, M., Fernandez-Muiños, T., Recha-Sancho, L., Lopez-Chicon, P., et al. (2013) Current Applications of Tissue Engineering in Biomedicine. J Biochip Tissue chip S2:004. doi: 10.4172/2153-0777.S2-004

18. Burdick, J., & Prestwich, G. (2011). Hyaluronic Acid Hydrogels for Biomedical Applications. Adv. Mater., 23, H41-H56. doi:10.1002/adma.201003963

19. Kim, I., Mauck, R., & Burdick, J. (2011). Hydrogel design for cartilage tissue engineering: A case study with hyaluronic acid. Biomaterials, 32(34), 8771-8782. doi:10.1016/j.biomaterials.2011.08.073