A Century-long Journey From the Discovery of Insulin to the Implantation of Stem Cell-derived Islets.

For the past century, insulin injections have saved millions of lives, but glycemic instability is still a persistent challenge for people with diabetes, leading to tremendous morbidity and premature mortality. Research in the field of islet transplantation has demonstrated that replacing insulin-producing ß cells can restore euglycemia comparable to individuals without diabetes. However, a short supply of cadaveric islet donors, the technically challenging process of isolating islets, and the requirement for chronic immune suppression have impeded widespread clinical adoption. Rather than relying on cadaveric cells, pluripotent stem cells could serve as a virtually unlimited supply of insulin-producing ß cells. Protocols have been developed that mimic the normal in vivo development of the human pancreas to generate pancreatic progenitor cells in vitro. Ongoing investigations have yielded progressively more mature ß-like cells in vitro that produce insulin but do not yet fully mimic healthy mature ß cells. Alongside development of differentiation protocols, other work has provided insight into potential implantation sites for stem cell-derived islet cells including the subcutaneous space, portal vein, and omentum. To optimize implanted cell survival and function, development of immune modulation therapies is ongoing, including selection of immunomodulatory medications and genetic modification of implanted cells to evade immune responses. Further, macroencapsulation or microencapsulation devices could be used to contain and/or immunoprotect implanted cells from the immune response including by using 3-dimensional bioprinting to facilitate the process. Remarkably, ongoing clinical trials have now yielded the first patient relying on differentiated stem cells rather than syringes as their insulin replacement therapy.

Comparison of Linear and 4-Arm Star Poly(vinyl pyrrolidone) for Aqueous Binder Jetting Additive Manufacturing of Personalized Dosage Tablets.

Fabrication of personalized dosage oral pharmaceuticals using additive manufacturing (AM) provides patients with customizable, locally manufactured, and cost-efficient tablets, while reducing the probability of side effects. Binder jetting AM has potential for fabrication of customized dosage tablets, but the resulting products lack in strength due to solely relying on the binder to produce structural integrity. The selection of polymeric binders is also limited due to viscosity restraints, which limits molecular weight and concentration. To investigate and ameliorate these limitations, this article reports a comprehensive study of linear and 4-arm star poly(vinyl pyrrolidone) (PVP) over a range of molecular weights as polymeric binders for binder jetting AM and their effect on physical tablet properties. Formulation of varying molecular weights and concentrations of linear and 4-arm star PVP in deionized water and subsequent jetting revealed relationships between the critical overlap concentrations (C*) and jettability on binder jetting systems with thermal inkjet printheads. After printing with a commercially available ZCorp Spectrum Z510 printer with an HP11 printhead with a lactose and powdered sugar powder bed, subsequent measurement of compressive strength, compressive modulus, and porosity revealed structure-property relationships between molecular weight, polymer concentration, and linear and 4-arm star architectures with physical properties of binder jetted tablets. This study elucidated that the dominating factor to increase compressive strength of a tablet is dependent on the weight percent of the polymer in the binder, which filled interstitial voids between powder particles. Because 4-arm star polymers have lower solution viscosities compared to linear analogues at the same molecular weights, they were jettable at higher concentrations, thus producing the strongest tablets at a compressive strength of 1.2 MPa. Finally, the inclusion of an active pharmaceutical ingredient (API), acetaminophen, revealed maintenance of the tablet physical properties across 5-50 total wt % API in each tablet.