Investigation of Magnet-driven and Image-guided Degradable Microrobots for the Precise Delivery of Therapeutic Cells

Abstract

Precise delivery of therapeutic cells to the target site in vivo is an emerging and promising cellular therapy in precision medicine. This technique, where cells can sense and respond to diseases dynamically, confer fewer side effects on the host compared with traditional chemotherapy or radiotherapy. This challenging issue can be solved using a specifically designed magnetic microcarrier that allows preferred residence of cells and preservation of cell functions while voyaging via vascular circulation. The use of degradable microrobots can enable treatment dosage of cells to access hard-to-reach tissues or human cavities and be degraded after minimally invasive medical treatments. Further, to precisely deliver cells into targeted site, an in vivo imaging technology must be used to visually trace the microrobot in transportation. This thesis presents the development of a magnet-driven and image-guided degradable microrobot that can precisely deliver engineered stem cells for orthotopic liver tumor treatment. The three aspects involved in this study are described as follows.

First, a degradable microrobot that used a burr-like porous spherical structure was designed to achieve biodegradability for in vivo applications, mechanical strength for carrying cells, and magnetic actuation capability. Polyethylene glycol (PEG) was used as basal biodegradable polymer, while diacrylate-derived PEG (PEGDA) and pentaerythritol triacrylate (PETA) were combined to adjust the degradability and mechanical strength. Fe₃O₄ nanoparticles were added to the polymer to achieve magnetic actuation. After considering microrobot mechanical strength, actuation capability requirements as well as fabrication constrains, the composition of the material was finalized at 74 vol% PEGDA, 24 vol% PETA, and 2 vol% Fe₃O₄ nanoparticles. The degradability and biocompatibility of the fabricated microrobots were also evaluated in depth in vitro and in vivo.

Second, the structure of the microrobot was optimized based on cell loading capacity. The key parameters of the microrobot, i.e., grid length and burr length, which determine the microrobot model, were optimized based on the maximum loading of therapeutic cells. A series of microrobots with different grid and burr lengths was used to load the same density of cells and determine the optimized microrobot size. Experiments of releasing cells from the microrobots were performed using an in vitro cultivation system to verify the effectiveness of the designed microrobots. Experimental results indicated that the carried cells were spontaneously released from the microrobots into the liver tissue. The precise navigation of the microrobots into the targeted site was also demonstrated in vitro and ex vivo.

Third, in vivo experiments of the microrobots carrying therapeutic cells were conducted for preclinical application on living animals. Under the guidance of a unique photoacoustic imaging technology, the cell-loaded microrobots could be actuated and imaged in a vascular environment of mouse, driven by an external gradient magnetic field system. The precise navigation of the microrobots to the targeted site was achieved. The therapeutic effect of the developed microrobots for cell delivery was subsequently verified in nude mice for cancer therapy. The experiment performed on nude mice implanted with orthotopic liver tumor at the left lateral lobe indicated the arrival of the microrobot onto the site, the release of cells into the tissues, and the evident inhibition of tumor growth.

In summary, this thesis reported the use of magnet-driven and image-guided degradable microrobots to deliver therapeutic cells for precision targeted therapy. The microrobot was designed to meet the requirements of degradability, mechanical strength, and magnetic actuation capability. The microrobots demonstrated the precise transportation of therapeutic cells into the targeted site, and the released cells from the microrobot onsite evidently inhibited orthotopic tumor growth in nude mice. The degradable microrobots could be used as a universal platform for targeted cellular therapy. This research can provide a reference for wireless and minimally invasive methods for precision therapy of diseases, such as cancer.

Date of Award	27 Jul 2020
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Dong SUN (Supervisor)