3D printed drug-loaded implantable devices for intraoperative treatment of cancer

Affiliations

¹ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill/North Carolina State University, Chapel Hill, NC 27599, USA.
² Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University School of Engineering, Stanford, CA 94305, USA; Carbon, Inc, Redwood City, CA 94063, USA. Electronic address: jmdesimone@stanford.edu.
⁷ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: andrew.wang2@utsouthwestern.edu.

PMID: 35217100
PMCID: PMC9373975
DOI: 10.1016/j.jconrel.2022.02.024

3D printed drug-loaded implantable devices for intraoperative treatment of cancer

C Tilden Hagan 4th et al. J Control Release. 2022 Apr.

. 2022 Apr:344:147-156.

doi: 10.1016/j.jconrel.2022.02.024. Epub 2022 Feb 22.

Authors

Affiliations

¹ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill/North Carolina State University, Chapel Hill, NC 27599, USA.
² Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University School of Engineering, Stanford, CA 94305, USA; Carbon, Inc, Redwood City, CA 94063, USA. Electronic address: jmdesimone@stanford.edu.
⁷ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: andrew.wang2@utsouthwestern.edu.

PMID: 35217100
PMCID: PMC9373975
DOI: 10.1016/j.jconrel.2022.02.024

Abstract

Surgery is an important treatment for cancer; however, local recurrence following macroscopically-complete resection is common and a significant cause of morbidity and mortality. Systemic chemotherapy is often employed as an adjuvant therapy to prevent recurrence of residual disease, but has limited efficacy due to poor penetration and dose-limiting off-target toxicities. Selective delivery of chemotherapeutics to the surgical bed may eliminate residual tumor cells while avoiding systemic toxicity. While this is challenging for traditional drug delivery technologies, we utilized advances in 3D printing and drug delivery science to engineer a drug-loaded arrowhead array device (AAD) to overcome these challenges. We demonstrated that such a device can be designed, fabricated, and implanted intraoperatively and provide extended release of chemotherapeutics directly to the resection area. Using paclitaxel and cisplatin as model drugs and murine models of cancer, we showed AADs significantly decreased local recurrence post-surgery and improved survival. We further demonstrated the potential for fabricating personalized AADs for intraoperative application in the clinical setting.

Keywords: 3D printing; Cancer; Continuous liquid interface production; Digital light synthesis; Drug-loaded device; Intraoperative chemotherapy; Personalized medicine.

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Conflict of interest statement

Competing interests

AZW is cofounder of Capio Biosciences and Archimmune Therapeutics. Neither is relevant to this work. JMD is co-founder and Chairman of the Board at Carbon, Inc. This work was conducted using Carbon 3D printing technology.

Figures

**Fig. 1.**
Arrowhead array devices. (a) 3D computer rendering of AAD. (b) Photograph of CLIP printed drug-loaded AAD. (c) SEM image (20×) of arrowhead array on AAD. (d) SEM image (100×) of arrowhead needle tip.

**Fig. 2.**
Treatment scheme and A431 tumor mouse model results. (a) Treatment scheme for the evaluation of drug-loaded AADs. Day 0 – Tumor inoculation through subcutaneous injection of 5×10⁴ A431 or 1×10⁶ 344SQ cells in 1:1 matrigel:medium. Day 7 – Tumors of 100–150 mm³ are surgically resected with half of these mice receiving AAD implants in their resection pockets and the other half receiving IV treatments. > Day 7 – Drug release from AADs. (made in ©BioRender – biorender.com) (b & c) A431 tumor mouse model. (b) Individual mouse tumor growth curves showing all drug-loaded AADs significantly reduce tumor recurrence. (c) Survival curve. All drug-loaded AADs showed significant survival benefits over its corresponding IV treatments. (* p < .05, *** p < .001)

**Fig. 3.**
344SQ tumor mouse model results. (a) IVIS luciferase fluorescence imaging 12 days post surgical resection showing decreased luminescence in drug-loaded AAD groups. (b) Individual mouse tumor growth curves showing all drug-loaded AADs significantly reduce tumor recurrence.

**Fig. 4.**
Real-time AADs for intraoperative application. Image sequence from initial photographs to device implantation in mouse and human models. Approximate tumor margins targeted for device implant are circled in yellow. (a) Photographs of mouse tumor resection area and human abdominal tumor resection cavity taken intraoperatively (sets of 37–46 images). Tumor margin is in circled area. (b) 3D rendered tissue model. Previously selected tumor margin is used as a model surface for a 3D drug-loaded AAD. (c) 3D computer model of implant device with needle array towards tissue. Shape was extracted from previously selected tumor margins. (d) 3D printed CLIP fabricated device ready for implant. (e) Device applied within tumor resection area (mouse only at this time).

See this image and copyright information in PMC

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3D printed drug-loaded implantable devices for intraoperative treatment of cancer

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3D printed drug-loaded implantable devices for intraoperative treatment of cancer

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Conflict of interest statement

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