AID systems must accommodate a wide range of insulin requirements safely and effectively to apply to a broad population. We evaluated glycemic outcomes among people ages 2 to 70y with T1D and baseline A1C<10% during a 3-mo home trial with the Omnipod 5 AID System, stratified by their baseline total daily insulin dose (TDD) during a 14-day standard therapy phase (ST, multiple daily injections or pump therapy) before AID use. No minimum TDD or weight was required to enter the study. Glycemic outcomes (time in range (TIR) 70-180 mg/dL, time below range (TBR) <70 mg/dL, time above range (TAR) >180 mg/dL) and change in TDD were evaluated across 6 ST TDD ranges, from <10U to ≥65U, during AID compared with ST. Participants (N=320) had a ST TDD of (mean ± SD) 34.8±21.7U (range 5.3-166.0U) . TDD during AID ranged from 5.0 to 110.7U; TDD increased slightly for those using <30U per day. TIR increased during AID across all TDD ranges (p<0.05, Table) . TAR and TBR were reduced in groups with TDD ≥10U and TDD ≥20U, respectively. Multiple linear regression indicated that older age and higher TIR during ST (both p<0.05) were associated with higher TIR during AID, while no relationship was found between ST TDD and TIR during AID (p=0.29, r2=0.57) . The Omnipod 5 System was safe and effective for a large cohort of people with T1D ages 2 to 70y across a wide range of insulin needs. Disclosure M.Schoelwer: Other Relationship; Dexcom, Inc., Research Support; Insulet Corporation, Medtronic, Tandem Diabetes Care, Inc. L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. J.Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Cecelia Health, Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Consultant; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Research Support; Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Speaker's Bureau; Lilly Diabetes. C.J.Levy: Advisory Panel; Dexcom, Inc., Eli Lilly and Company, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, T1D Exchange, Tandem Diabetes Care, Inc. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. S.A.Macleish: Advisory Panel; Insulet Corporation. D.Desalvo: Consultant; Dexcom, Inc., Insulet Corporation, Research Support; Insulet Corporation. V.Shah: Advisory Panel; Medscape, Sanofi, Consultant; Dexcom, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk. A.Bhargava: Research Support; Abbott Diabetes, AbbVie Inc., Boehringer Ingelheim International GmbH, Boston Therapeutics, Inc., Covance, Dexcom, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Insulet Corporation, Kowa Pharmaceuticals America, Inc., Lexicon Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Medtronic, Novo Nordisk, Poxel SA, Quintiles, Sanofi, Senseonics, Tolerion, Inc., Viking Therapeutics, vTv Therapeutics. T.C.Jones: None. G.Aleppo: Consultant; Insulet Corporation, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Fractyl Health, Inc., Insulet Corporation, Novo Nordisk, Speaker's Bureau; Dexcom, Inc. B.W.Bode: Advisory Panel; CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Consultant; Bigfoot Biomedical, Inc., Research Support; Abbott, Beta Bionics, Inc., Dexcom, Inc., Diasome, Dompé, Eli Lilly and Company, Insulet Corporation, IQVIA Inc., Jaeb Center for Health Research, Medtronic, Novo Nordisk, Provention Bio, Inc., REMD Biotherapeutics, Sanvita Medical, Senseonics, ViaCyte, Inc., Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; AgaMatrix, Glytec, LLC. R.E.Gurlin: Employee; Insulet Corporation. T.T.Ly: Employee; Insulet Corporation, Stock/Shareholder; Insulet Corporation. Omnipod 5 research group: n/a. A.L.Carlson: Advisory Panel; MannKind Corporation, Employee; Bright Health Group, Other Relationship; Medtronic, Research Support; Funding This study was funded by Insulet Corporation.

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. Impact statement Significant research developments in beta cell replacement therapies show its promise in providing a functional cure for type 1 diabetes (T1D); yet, their widespread clinical use has been difficult to achieve. This review provides a brief overview of the requirements for a beta cell replacement product followed by a discussion on both the promise and limitations of three-dimensional bioprinting in facilitating the fabrication of such products to enable translation into the clinic. Advancements in this area could be a key component to unlocking the safety and effectiveness of beta cell therapy for T1D.

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.

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.

Mitigation of the foreign body response (FBR) and successful tissue integration are essential to ensuring the longevity of implanted devices and biomaterials. The use of porous materials and coatings has been shown to have an impact, as the textured surfaces can mediate macrophage interactions with the implant and influence the FBR, and the pores can provide space for vascularization and tissue integration. In this study, we use a new class of implantable porous biomaterials templated from bicontinuous interfacially jammed emulsion gels (bijels), which offer a fully percolating, non-constricting porous network with a uniform pore diameter on the order of tens of micrometers, and surfaces with consistent curvature. We demonstrate that these unique morphological features, inherent to bijel-templated materials (BTMs), can enhance tissue integration and vascularization, and reduce the FBR. Cylindrical polyethylene glycol diacrylate (PEGDA) BTMs, along with PEGDA particle-templated materials (PTMs), and non-templated materials (NTMs), were implanted into the subcutaneous space of athymic nude mice. After 28 days, implants were retrieved and analyzed via histological techniques. Within BTMs, blood vessels of increased size and depth, changes in collagen deposition, and increased presence of pro-healing macrophages were observed compared to that of PTM and NTM implants. Bijel templating offers a new route to biomaterials that can improve the function and longevity of implantable devices. Statement of Significance All implanted biomaterials are subject to the foreign body response (FBR) which can have a detrimental effect on their efficacy. Altering the surface chemistry can decrease the FBR by limiting the amount of proteins adsorbed to the implant. This effect can be enhanced by including pores in the biomaterial to allow new tissue growth as the implant becomes integrated in the body. Here, we introduce a new class of self-assembled biomaterials comprising a fully penetrating, non-constricting pore phase with hyperbolic (saddle) surfaces for enhanced tissue integration. These unique morphological characteristics result in dense blood vessel formation and favorable tissue response properties demonstrated in a four-week implantation study. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

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.