Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform

Abstract

Fibrous capsule (FC) formation, secondary to the foreign body response (FBR), impedes molecular transport and is detrimental to the long-term efficacy of implantable drug delivery devices, especially when tunable, temporal control is necessary. We report the development of an implantable mechanotherapeutic drug delivery platform to mitigate and overcome this host immune response using two distinct, yet synergistic soft robotic strategies. Firstly, daily intermittent actuation (cycling at 1 Hz for 5 minutes every 12 hours) preserves long-term, rapid delivery of a model drug (insulin) over 8 weeks of implantation, by mediating local immunomodulation of the cellular FBR and inducing multiphasic temporal FC changes. Secondly, actuation-mediated rapid release of therapy can enhance mass transport and therapeutic effect with tunable, temporal control. In a step towards clinical translation, we utilise a minimally invasive percutaneous approach to implant a scaled-up device in a human cadaveric model. Our soft actuatable platform has potential clinical utility for a variety of indications where transport is affected by fibrosis, such as the management of type 1 diabetes.

Soft robot–mediated autonomous adaptation to fibrotic capsule formation for improved drug delivery

“…Soft robotics represents a particularly useful technology in this context, with the potential to gently and minimally invasively interact with soft tissues. Our laboratory has already shown the ability to alter biomechanical properties at an implant site by reducing fibrotic capsule formation using intermittent soft robotic actuation ( 1 , 18 ). We recently demonstrated that such mechanotherapy significantly improved drug delivery, resulting in near-complete preservation of implanted device–mediated drug delivery in a mouse model over an 8-week period ( 18 ).…”

“…Our laboratory has already shown the ability to alter biomechanical properties at an implant site by reducing fibrotic capsule formation using intermittent soft robotic actuation ( 1 , 18 ). We recently demonstrated that such mechanotherapy significantly improved drug delivery, resulting in near-complete preservation of implanted device–mediated drug delivery in a mouse model over an 8-week period ( 18 ). This technique can also increase mass transport and therapeutic effect via on-demand actuations that enable rapid release of a large bolus of drug, even in the presence of the fibrotic capsule ( 18 ).…”

“…We recently demonstrated that such mechanotherapy significantly improved drug delivery, resulting in near-complete preservation of implanted device–mediated drug delivery in a mouse model over an 8-week period ( 18 ). This technique can also increase mass transport and therapeutic effect via on-demand actuations that enable rapid release of a large bolus of drug, even in the presence of the fibrotic capsule ( 18 ). However, these strategies are largely unguided, using a predetermined actuation regimen, which does not account for patient or implant site variability or the progressive nature of the foreign body response.…”

“…Pressure to the actuatable reservoir compresses the inner therapeutic reservoir to release drug (Fig. 1B and movies S1 and S2) ( 1 , 18 ). The FSDSR (Fig.…”

“…1C and fig. S1, C and D) advances substantially on previous iterations of our mechanotherapeutic implant ( 18 ) by using the principles of electrochemical impedance spectroscopy to quantify fibrotic capsule formation and the resulting degree of porous membrane occlusion. Electrochemical impedance spectroscopy is a noninvasive technique used to characterize electrical properties of materials ( 23 , 24 ) through impedance (Z), which measures the opposition to electrical movement in a system ( 23 ).…”