Intermittent actuation attenuates fibrotic behaviour of myofibroblasts.

The foreign body response (FBR) to implanted materials culminates in the deposition of a hypo-permeable, collagen rich fibrotic capsule by myofibroblast cells at the implant site. The fibrotic capsule can be deleterious to the function of some medical implants as it can isolate the implant from the host environment. Modulation of fibrotic capsule formation has been achieved using intermittent actuation of drug delivery implants, however the mechanisms underlying this response are not well understood. Here, we use analytical, computational, and in vitro models to understand the response of human myofibroblasts (WPMY-1 stromal cell line) to intermittent actuation using soft robotics and investigate how actuation can alter the secretion of collagen and pro/anti-inflammatory cytokines by these cells. Our findings suggest that there is a mechanical loading threshold that can modulate the fibrotic behaviour of myofibroblasts, by reducing the secretion of soluble collagen, transforming growth factor beta-1 and interleukin 1-beta, and upregulating the anti-inflammatory interleukin-10. By improving our understanding of how cells involved in the FBR respond to mechanical actuation, we can harness this technology to improve functional outcomes for a wide range of implanted medical device applications including drug delivery and cell encapsulation platforms. STATEMENT OF SIGNIFICANCE: A major barrier to the successful clinical translation of many implantable medical devices is the foreign body response (FBR) and resultant deposition of a hypo-permeable fibrotic capsule (FC) around the implant. Perturbation of the implant site using intermittent actuation (IA) of soft-robotic implants has previously been shown to modulate the FBR and reduce FC thickness. However, the mechanisms of action underlying this response were largely unknown. Here, we investigate how IA can alter the activity of myofibroblast cells, and ultimately suggest that there is a mechanical loading threshold within which their fibrotic behaviour can be modulated. These findings can be harnessed to improve functional outcomes for a wide range of medical implants, particularly drug delivery and cell encapsulation devices.

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

The foreign body response impedes the function and longevity of implantable drug delivery devices. As a dense fibrotic capsule forms, integration of the device with the host tissue becomes compromised, ultimately resulting in device seclusion and treatment failure. We present FibroSensing Dynamic Soft Reservoir (FSDSR), an implantable drug delivery device capable of monitoring fibrotic capsule formation and overcoming its effects via soft robotic actuations. Occlusion of the FSDSR porous membrane was monitored over 7 days in a rodent model using electrochemical impedance spectroscopy. The electrical resistance of the fibrotic capsule correlated to its increase in thickness and volume. Our FibroSensing membrane showed great sensitivity in detecting changes at the abiotic/biotic interface, such as collagen deposition and myofibroblast proliferation. The potential of the FSDSR to overcome fibrotic capsule formation and maintain constant drug dosing over time was demonstrated in silico and in vitro. Controlled closed loop release of methylene blue into agarose gels (with a comparable fold change in permeability relating to 7 and 28 days in vivo) was achieved by adjusting the magnitude and frequency of pneumatic actuations after impedance measurements by the FibroSensing membrane. By sensing fibrotic capsule formation in vivo, the FSDSR will be capable of probing and adapting to the foreign body response through dynamic actuation changes. Informed by real-time sensor signals, this device offers the potential for long-term efficacy and sustained drug dosing, even in the setting of fibrotic capsule formation.