What: FlexFlow, a vascularized insulin delivery catheter
Why: To replace unreliable insulin infusion sets with a game-changing technology
Who: In Collaboration with Professor Ali Mohraz
How: A new class of materials
Background: Type 1 Diabetes (T1D) is an autoimmune disease affecting an estimated 1.25 million people in the United States. Roughly 1 million of those people manage their blood-glucose using continuous subcutaneous insulin infusion (CSII) pumps[1]. These pumps are rapidly improving from patient-controlled insulin delivering machinery to fully automated closed loop algorithms constantly adjusting insulin administration rate for autonomous blood-glucose regulation. Insulin infusion sets (IIS) are devices that are used as the conduit to deliver insulin subcutaneously from the reservoir of a CSII pump. Problems arise when this delivery chain is impeded, and insulin is unable to be picked up by the circulatory system. This can happen either with a kink of the cannula or blockage by fibrotic tissue deposited by the body as part of the foreign body response (FBR). These factors can lead to unexpected hyperglycemic events where the blood-glucose concentration rises above safe levels leading to headaches, confusion, coma, or death[2], [3]. Alternatively, the trapped insulin can be released causing a hypoglycemic event where the blood-glucose concentration drops below safe levels causing seizures, loss of consciousness, and death[2], [3]. Due to the risk of infection and unresponsive glucose levels to insulin administration, commercial units are recommended to be changed every 2-3 days. The need for new infusion set technology is regularly requested by patients and advocates who argue IIS improvements are long overdue[3]
FlexFlow: To address this need, we have developed a collaboration with Dr. Ali Mohraz at the Soft Matter Engineering Laboratory (SMEL) to develop a novel IIS we call FlexFlow. FlexFlow incorporates a bijel-templated material (BTM) that both fills and protrudes from the infusion set cannula (Fig 1.). The bijel, or Bicontinuous Interfacially Jammed Emulsion Gel, is a unique class of soft materials that come about during the spinodal decomposition of two immiscible fluids in the presence of neutrally wetting colloid particles[4]. During this quenching process, the two fluids separate into two non-constricting, continuous regions with uniform curvature. The selective polymerization of one of the regions creates a polymer/void construct, known as a bijel-templated material (BTM) that can be used for the purpose of biomaterial implementation and tissue engineering (Fig. 2)[5].
Previous research has demonstrated specific advantages of BTMs that have the potential to improve insulin pump therapy. The unique microstructure of bicontinuous domains can be tuned depending on the volume fraction of the particles[4], [5]. Additionally, the non-constricting porous architecture and uniform curvature [5] has been shown to quiet the immune system (Fig. 3) by promoting the macrophage M2 phenotype[6], allowing vascularized tissue integration, reducing fat and scar tissue build up (Fig 4)[6], and adding structural stability to prevent kinking (fig. 5).
For these reasons, we are engineering a long lasting insulin infusion set that may reduce unwanted hyper- and hypo- glycemic events, unexpected cannula kinking and scar tissue buildup while simultaneously improving insulin kinetics, and the quality of life for those living with Type 1 Diabetes.
In support of the BTM applications projects, the fundamental cell-BTM interface interaction is being probed via computational modeling (Fig.6) Using coupled differential equations in a 3D phase-field model, cell behavior related to substrate interactions’ impact on cytoskeletal components is modeled in an effort to relate the unique topography of BTMs to the improved immune response seen in implant studies (less fibrosis, higher ratio of M2 wound-healing type macrophages). The success of this effort would inform improvements to implant success on a broad scale. This work is in collaboration with Professor Anya Grosberg, UCI BME.
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[1] “Facts,” JDRF. https://www.jdrf.org/t1d-resources/about/facts/ (accessed Jul. 23, 2021).
[2] A. Ziegler, T. Williams, N. Yarid, D. L. Schultz, and E. A. Bundock, “Fatalities Due to Failure of Continuous Subcutaneous Insulin Infusion Devices: A Report of Six Cases,” J. Forensic Sci., vol. 64, no. 1, pp. 275–280, 2019, doi: 10.1111/1556-4029.13841.
[3] “Insulin Infusion Set: The Achilles Heel of Continuous Subcutaneous Insulin Infusion – Lutz Heinemann, Lars Krinelke, 2012.” https://journals.sagepub.com/doi/10.1177/193229681200600429?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed (accessed Jul. 23, 2021).
[4] E. M. Herzig, K. A. White, A. B. Schofield, W. C. K. Poon, and P. S. Clegg, “Bicontinuous emulsions stabilized solely by colloidal particles,” Nat. Mater., vol. 6, no. 12, pp. 966–971, Dec. 2007, doi: 10.1038/nmat2055.
[5] “Bicontinuous Macroporous Materials from Bijel Templates – Google Search.” https://www.google.com/search?q=Bicontinuous+Macroporous+Materials+from+Bijel+Templates&rlz=1C1CHBF_enUS897US897&oq=Bicontinuous+Macroporous+Materials+from+Bijel+Templates&aqs=chrome..69i57.447j0j7&sourceid=chrome&ie=UTF-8 (accessed Jul. 23, 2021).
[6] T. J. Thorson, R. E. Gurlin, E. L. Botvinick, and A. Mohraz, “Bijel-templated implantable biomaterials for enhancing tissue integration and vascularization,” Acta Biomater., vol. 94, pp. 173–182, Aug. 2019, doi: 10.1016/j.actbio.2019.06.031.