An interventional image‐guided microdevice implantation and retrieval method for in‐vivo drug response assessment

Abstract

Purpose: Recently developed implantable microdevices can perform multi-drug response assessment of cancer drugs in-vivo, with potential to develop highly optimized personalized cancer treatment strategies. However, minimally invasive/interventional image-guided methods of in-vivo microdevice implantation, securement, and retrieval are needed for broad clinical translation. Here we demonstrate proof-of-concept of an interventional microdevice implantation and retrieval method for personalized drug response assessment, using ex-vivo phantom, ex-vivo tissue, and in-vivo murine models. Methods: A method for minimally-invasive microdevice implantation and retrieval was developed, by which a custom-prototyped 6 mm retrievable microdevice can be implanted into a live tumor, deliver drugs into 10 discrete regions of adjacent tissue, and retrieved along with the adjacent drug-exposed tissue with a custom-prototyped retrieval needle device to allow in-vivo multidrug response assessment. Computed tomography (CT) and ultrasound (US)-guided minimally invasive microdevice implantation and retrieval were tested in ex-vivo phantom and tissue models. Successful retrieval was defined as retrieval of the microdevice and adjacent core phantom/tissue sample containing at least 4/10 drug delivery sites. Subsequently, 10 implantation and retrieval trials in phantom models were performed using bi-axial and tri-axial retrieval needles; success rates were calculated and compared using a two-proportion z-test and the number of successfully retrieved drug release sites per microdevice was calculated and compared using a one-tailed independent t-test. Finally, five microdevices, each containing ten reservoirs preloaded with chemotherapy agent Doxorubicin, were implanted into mouse tumors in-vivo, secured for 24-h during drug release, and microdevice/tissue retrieval was performed under ultrasound guidance. Fluorescence microscopy of the retrieved tissue was used to confirm drug delivery and apoptosis staining assessed in-vivo tissue response; correlation of drug release and apoptosis staining were used to assess in-vivo drug efficacy. Results: Image-guided microdevice implantation and retrieval were successful in ex-vivo phantom and tissue models with both US and CT guidance. Bi-axial retrieval success rate was significantly higher than triaxial retrieval in ex-vivo phantom trials (90% vs 50%, z = 1.95, P = 0.026), and had nonsignificantly higher number of retrieved drug-release sites per microdevice (8.3 vs 7.0, t = 1.37, P = 0.097). Bi-axial retrieval was successful in all five in-vivo mouse tumor models, and allowed invivo drug response assessment at up to ten discrete drug delivery sites per microdevice. An average of 6.8/10 discrete tumor sites containing micro-doses of delivered drug were retrieved per in-vivo attempt (min 5, max 10, std 1.93). Tissue regions of drug delivery, as assessed with fluorescent Doxorubicin drug signal, correlated with regions of apoptosis staining in all in-vivo models, indicating drug efficacy. No bleeding,...

Self-Expanding Anchors for Stabilizing Percutaneously Implanted Microdevices in Biological Tissues

“…The drug-screening IMD was machined as previously described [ 7 , 14 ]. Solidworks (Dassault Systems, Inc., Waltham, MA, USA) and Mastercam (CNC Software, Inc., Tolland, CT, USA) were used to develop computer-aided design and manufacture inputs.…”

“…At its proximal end, the microdevice body is attached to a 0.008 inchdiameter, 10 cm long nitinol wire (Malin Co., Cleveland, OH, USA). After microdevice delivery, this wire is left externalized and enables minimally invasive retrieval of the microdevice, as previously described [ 14 ]. In this study, traction on this wire is used produce tensile force on the microdevice to test stability, as described below.…”

“…It has also allowed enrollment of a greater number of patients into early clinical trials evaluating the feasibility of the drug-screening IMD [ 11 , 12 , 13 ], and should allow more widespread adoption of this technology in a clinical setting. In addition, a recently developed minimally invasive retrieval method allows non-surgical removal of the IMD [ 14 ]. With these advances, the IMD and similar implanted devices can be placed and removed (if appropriate) in a relatively safe manner that minimizes procedural risk and recovery time.…”

A Miniaturized Platform for Multiplexed Drug Response Imaging in Live Tumors

“…Drug formulations are loaded into these reservoirs in solid powder form as described in Methods and are passively released into spatially distinct microscopic regions of tissue after tumor implantation. The reservoir dimensions and spacing and are optimized based on prior studies evaluating drug diffusion [3,4,17], with sufficient separation to ensure that there is no spatial overlap between drug release sites.…”

“…The drugs were reconstituted with polyethylene glycol (PEG) and loaded in a solid-powder form. The drug formulation was selected in a manner that has been previously shown to contain local drug diffusion to within 100-400 μm radially of the drug release sites, and has been shown to approximate systemic dosing at these depths (see Methods) [3][4][5]17]. Specific drug responses to three chemotherapy agents could be tested in each tumor, since each device had three unique drug release sites.…”