Accelerated absorption of regular insulin administered via a vascularizing permeable microchamber implanted subcutaneously in diabeticRattus norvegicus

Abstract

In Type 1 diabetes patients, even ultra-rapid acting insulins injected subcutaneously reach peak concentrations in 45 minutes or longer. The lag time between dosing and peak concentration, as well as intra- and inter-subject variability, render prandial glucose control and dose consistency difficult. We postulated that insulin absorption from subcutaneously implantable vascularizing microchambers would be significantly faster than conventional subcutaneous injection. Male athymic nude R. norvegicus rendered diabetic with streptozotocin were implanted with vascularizing microchambers (single chamber; 1.5 cm2 surface area per side; nominal volume, 22.5 µL). Plasma insulin was assayed after a single dose (1.5 U/kg) of diluted insulin human (Humulin®R U-100), injected subcutaneously or via microchamber. Microchambers were also implanted in additional animals and retrieved at intervals for histologic assessment of vascularity. Following conventional subcutaneous injection, the mean peak insulin concentration was 22.7 (SD 14.2) minutes. By contrast, when identical doses of insulin were injected via subcutaneous microchamber 28 days after implantation, the mean peak insulin time was shortened to 7.50 (SD 4.52) minutes. Peak insulin concentrations were similar by either route; however, inter-subject variability was reduced when insulin was administered via microchamber. Histologic examination of tissue surrounding microchambers showed mature vascularization on days 21 and 40 post-implantation. Implantable vascularizing microchambers of similar design may prove clinically useful for insulin dosing, either intermittently by needle, or continuously by pump including in “closed loop” systems, such as the artificial pancreas.

VEGF‐delivering PEG hydrogels promote vascularization in the porcine subcutaneous space

“…Indeed, enhancing the connection between insulin‐producing cells and host vasculature has been shown to help the delivered cells sense glucose, transport therapeutic paracrine/endocrine factors, and secrete insulin on demand 18 . In addition to increasing the survival of delivered cells, vascularizing the subcutaneous space enhances medication absorption; Steyn et al found that implantable, vascularizing microchambers rapidly increased exogenous insulin uptake compared to conventional subcutaneous injections 19 . As such, strategies to increase vascularization in the subcutaneous space have been pursued and are summarized in the subsequent paragraph.…”

“…18 In addition to increasing the survival of delivered cells, vascularizing the subcutaneous space enhances medication absorption; Steyn et al found that implantable, vascularizing microchambers rapidly increased exogenous insulin uptake compared to conventional subcutaneous injections. 19 As such, strategies to increase vascularization in the subcutaneous space have been pursued and are summarized in the subsequent paragraph. To prioritize clinical translation, any vascularization strategy must minimize technical, safety, and regulatory burdens.…”