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Type 1 diabetes (T1D) is an autoimmune disorder in which the body's own immune system selectively attacks beta cells within pancreatic islets resulting in insufficient insulin production and loss of the ability to regulate blood glucose (BG) levels. Currently, the standard of care consists of BG level monitoring and insulin administration, which are essential to avoid the consequences of dysglycemia and long-term complications. Although recent advances in continuous glucose monitoring and automated insulin delivery systems have resulted in improved clinical outcomes for users, nearly 80% of people with T1D fail to achieve their target hemoglobin A1c (HbA1c) levels defined by the American Diabetes Association. Intraportal islet transplantation into immunosuppressed individuals with T1D suffering from impaired awareness of hypoglycemia has resulted in lower HbA1c, elimination of severe hypoglycemic events, and insulin independence, demonstrating the unique potential of beta cell replacement therapy (BCRT) in providing optimal glycemic control and a functional cure for T1D. BCRTs need to maximize cell engraftment, long-term survival, and function in the absence of immunosuppression to provide meaningful clinical outcomes to all people living with T1D. One innovative technology that could enable widespread translation of this approach into the clinic is three-dimensional (3D) bioprinting. Herein, we review how bioprinting could facilitate translation of BCRTs as well as the current and forthcoming techniques used for bioprinting of a BCRT product. We discuss the strengths and weaknesses of 3D bioprinting in this context in addition to the road ahead for the development of BCRTs.

Type 1 diabetic patients with severe hypoglycemia unawareness have benefitted from cellular therapies, such as pancreas or islet transplantation; however, donor shortage and the need for immunosuppression limits widespread clinical application. We previously developed an intravascular bioartificial pancreas (iBAP) using silicon nanopore membranes (SNM) for immunoprotection. To ensure ample nutrient delivery, the iBAP will need a cell scaffold with high hydraulic permeability to provide mechanical support and maintain islet viability and function. Here, we examine the feasibility of superporous agarose (SPA) as a potential cell scaffold in the iBAP. SPA exhibits 66‐fold greater hydraulic permeability than the SNM along with a short (<10 μm) diffusion distance to the nearest islet. SPA also supports short‐term functionality of both encapsulated human islets and stem‐cell‐derived enriched β‐clusters in a convection‐based system, demonstrated by high viability (>95%) and biphasic insulin responses to dynamic glucose stimulus. These findings suggest that the SPA scaffold will not limit nutrient delivery in a convection‐based bioartificial pancreas and merits continued investigation.

Success of cell therapy in avascular sites will depend on providing sufficient blood supply to transplanted tissues. A popular strategy of providing blood supply is to embed cells within a functionalized hydrogel implanted within the host to stimulate neovascularization. However, hydrogel systems are not always amenable for removal post-transplantation; thus, it may be advantageous to implant a device that contains cells while also providing access to the circulation so retrieval is possible. Here we investigate one instance of providing access to a vessel network, a thin sheet with through-cut slits, and determine if it can be vascularized from autologous materials. We compared the effect of slit width on vascularization of a thin sheet following subcutaneous implantation into an animal model. Polydimethylsiloxane sheets with varying slit widths (approximately 150, 300, 500, or 1500 µm) were fabricated from three-dimensional printed molds. Subcutaneous implantation of sheets in immunodeficient mice revealed that smaller slit widths have evidence of angiogenesis and new tissue growth, while larger slit widths contain native mature tissue squeezing into the space. Our results show that engineered slit sheets may provide a simple approach to cell transplantation by providing a prevascularized and innervated environment.

Abstract:Prevascularized medical devices can improve cell therapy. Such devices may replace whole organ transplantation with hosting only the necessary therapeutic cells. We have developed a noninvasive optical technology to study the vascularization into such medical devices. In our technique, oxygen partial pressure within a device is monitored by Oxygen Sensitive Tubes (OSTs), comprising oxygen permeable silicone tubing with inner luminal surfaces coated by an oxygen-sensitive porphyrin dye. OSTs were placed within a PDMS device and transplanted into the subcutaneous space of athymic nude mice. An optical probe placed over the skin excites the OSTs with a pulse of light and detects the luminescent lifetime of emitted light, which is uniquely related to oxygen partial pressure. Furthermore, we developed a Dynamic Inhalation Gas Test (DIGT) to determine the oxygen transport rate between the microvasculature and the device. DIGT works by monitoring oxygen partial pressure in a device following a step change in inhaled-gas oxygen content. We report DIGT oxygen dynamics measured intermittently over eight weeks. Our study shows DIGT dynamics are unique to each implant, supporting the important role of the host tissue response in the availability of oxygen over time.

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