Bio-inspired design of a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes Minglin Ma Biological and Environmental Engineering, Cornell University Statement of Purpose: Cell encapsulation has been glucagon in the islets retrieved from both kidney capsule shown to hold promise for effective, long-term treatment and TRAFFIC, similar to the islets before transplantation. Human islets - kidney capsule (n=9) 500 Human islets - TRAFFIC (n=10) c Insulin Nkx6.1 of type 1 diabetes (T1D) (1-4), an unrelenting disease that a Non-diabetic control (n=4) Glucagon 450 Diabetic control (n=21) *# Nucleus 400 Transplantation Before affects millions of people. However, encapsulating 350 transplantation 300 systems developed to date still face various challenges. 250 100 µm 100 µm 200 150 Insulin Nkx6.1 For example, alginate hydrogel capsules, despite their 100 Glucagon Nucleus 0 20 40 60 80 100 120 140 160 180 Retrieved from biocompatibility and function, are difficult to retrieve or (mg/dL) glucose concentration Blood Time after STZ injections (day) Human islets - kidney capsule (n=9) Kidney capsule b Human islets - TRAFFIC (n=10) Non-diabetic control (n=4) 30 #* Diabetic control (n=21) replace in completeness due to the large number of 100 µm 100 µm 28 Transplantation 26 Insulin Nkx6.1 capsules required for effective treatment and the Glucagon 24 Nucleus complicated organ structures in the transplantation site 22 Retrieved from TRAFFIC Body weight weight (g) Body 20 18 (i.e. peritoneal space), contributing to risks and concerns 100 µm 100 µm 0 20 40 60 80 100 120 140 160 180 in case of transplant failure or medical complications. On Time post STZ injections (day) the other hand, macroscopic devices (e.g. planar diffusion Figure 1. Demonstration of therapeutic potential of chambers), although considered retrievable, are TRAFFIC using human islets. a, Blood glucose challenging to scale up to a clinically relevant capacity concentrations of diabetic SCID-Beige mice after due to their small surface area for mass transfer. Here, we transplantation of human islets, n=4-21, mean ± s.e.m., report a new and simple cell encapsulation design, termed *P<0.05 (human islets – TRAFFIC versus diabetic as TRAFFIC, that is readily scalable and conveniently control), #P>0.05 (human islets – kidney capsule versus retrievable (through a minimally invasive laparoscopic human islets - TRAFFIC). b, Body weights of the mice procedure). This encapsulation device may contribute to a after transplantation. n=4-21, mean ± s.e.m., *P<0.05 cellular therapy for T1D and potentially other endocrine (human islets – TRAFFIC versus diabetic control), disorders and hormone deficient diseases. #P>0.05 (human islets – kidney capsule versus human Methods: The key to the TRAFFIC design, inspired by islets - TRAFFIC) c, H&E staining and water-collecting spider silks, was to engineer a highly immunohistochemical staining of human islets before wettable, Ca2+-releasing nanoporous polymer thread that transplantation and retrieved from kidney capsules or promoted uniform in situ crosslinking and strong TRAFFIC. adhesion of a thin layer of alginate hydrogel around the Due to the thin cylindrical geometry, TRAFFIC can be thread. We demonstrated robust mechanical and mass scaled up in the longitudinal direction to any capacity or transfer properties of the device as well as its durable length and can still be retrieved through minimally functions in diabetic mice. We further showed, as a proof invasive laparoscopic procedures. To prove this concept, of concept, scalability and retrievability in a dog we fabricated ~10-inch TRAFFIC devices performed implantation model. large animal experiments using a canine intraperitoneal Results: After confirming the mechanical robustness, implantation model. We showed convenient retrieval of biocompatibility, and mass transfer property of the devices from dogs. TRAFFIC, we explored its therapeutic potential using two Conclusions: In this work, we report a bio-inspired transplantation models. We transplanted encapsulated rat design that takes advantages of alginate hydrogel and is islets streptozotocin (STZ)-induced C57BL/6 diabetic both scalable and retrievable. We believe this new mice or human islets into SCID-Beige diabetic mice. For encapsulation design will not only allow the delivery of C57BL/6 diabetic mice, each mouse received a device of sufficient cell mass for patients but also minimize the ~1-inch length containing approximately 500 islet risks and discomfort associated with transplantation, equivalents (IEQ’s). The blood glucose (BG) level of the make repeated transplantation a more acceptable option, mice decreased to the normal glycemic range (BG<200 and therefore likely accelerate and contribute to the mg/dL) 2 days after the transplantation and the mice translation of cell encapsulation for T1D and potentially remained cured for 4 weeks before the devices were many other diseases. retrieved. After retrieval, the mice returned to a diabetic state, indicating the effectiveness of the device in References: (1) Desai T & Shea LD (2017) Advances in regulating the BG. For SCID-Beige mice, each mouse islet encapsulation technologies. Nat. Rev. Drug Discov. received 2 devices of ~1-inch-long containing around 16:338–350. (2) Orive G, et al. (2003) Cell encapsulation: 2,000 IEQ’s in total. Non-encapsulated human islets of a Promise and progress. Nat. Med. 9(1):104-107. (3). similar number were transplanted in kidney capsules as Dolgin E (2014) ENCAPSULATE THIS. Nat. Med. control. The BG and body weight were monitored over 20(1):9-11. (4) Scharp DW & Marchetti P (2014) time (Fig 1). The hyperglycemia was reversed ~2 weeks Encapsulated islets for diabetes therapy: History, current after transplantation and the BG levels were maintained progress, and critical issues requiring solution. Adv. Drug within the normal range for more than 4 months before Deliv. Rev. 67-68:35-73. the device retrieval. Immunohistochemical staining showed positive staining of human insulin, Nkx-6.1, and .