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WIREs Nanomed Nanobiotechnol

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Microchips and controlled‐release drug reservoirs

Advanced Review

Mark Staples

Published Online: Jun 17 2010

DOI: 10.1002/wnan.93

Full article on Wiley Online Library: HTML PDF

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Abstract This review summarizes and updates the development of implantable microchip‐containing devices that control dosing from drug reservoirs integrated with the devices. As the expense and risk of new drug development continues to increase, technologies that make the best use of existing therapeutics may add significant value. Trends of future medical care that may require advanced drug delivery systems include individualized therapy and the capability to automate drug delivery. Implantable drug delivery devices that promise to address these anticipated needs have been constructed in a variety of ways using micro‐ and nanoelectromechanical systems (MEMS or NEMS)‐based technology. These devices expand treatment options for addressing unmet medical needs related to dosing. Within the last few years, advances in several technologies (MEMS or NEMS fabrication, materials science, polymer chemistry, and data management) have converged to enable the construction of miniaturized implantable devices for controlled delivery of therapeutic agents from one or more reservoirs. Suboptimal performance of conventional dosing methods in terms of safety, efficacy, pain, or convenience can be improved with advanced delivery devices. Microchip‐based implantable drug delivery devices allow localized delivery by direct placement of the device at the treatment site, delivery on demand (emergency administration, pulsatile, or adjustable continuous dosing), programmable dosing cycles, automated delivery of multiple drugs, and dosing in response to physiological and diagnostic feedback. In addition, innovative drug‐medical device combinations may protect labile active ingredients within hermetically sealed reservoirs. WIREs Nanomed Nanobiotechnol 2010 2 400–417 This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants

Final packaged implantable rapid drug delivery device. With kind permission from Springer Science + Business Media: Elman NM, Ho Duc HL, Cima MJ. An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care. (Reprinted with permission from Ref 21. Copyright 2009 Springer Science + Business Media).

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Three independent release events show the reproducible pulsatile release of hPTH 34‐amino acid N‐terminal fragment, hPTH(1–34) from a single multireservoir array. (Reprinted with permission from Ref 102. Copyright 2008 Springer).

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Exterior (left) and interior (right) views of assembled system: implantable multireservoir microchip drug delivery device. (Adapted with permission from Ref 68. Copyright 2006 Macmillan Publishers Ltd.).

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A representative section of a reservoir‐based microchip. Reprinted from Maloney JM, Uhland SA, Polito BF, Sheppard NF Jr, Pelta CM, et al. Electrothermally activated microchips for implantable drug delivery and biosensing. (Reprinted with permission from Ref 98. Copyright 2005 Elsevier).

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Schematic of shape memory (SMA) alloy actuation micropump. With kind permission from Springer Science + Business Media: Amirouche F, Zhou Y, Johnson T. Current micropump technologies and their biomedical applications. (Reprinted with permission from Ref 58. Copyright 2009 Springer Science + Business Media).

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Debiotech miniature infusion pump (MIP) micropump: an implantable drug delivery system (IDDS). Debiotech products page. Available at: http://www.debiotech.com/products/msys/mip.html. (Accessed February 1, 2010. ©Copyright 1995–2002 Debiotech S.A. All rights reserved).

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Pulsatile release of sulfosalicylic acid (SSA; open triangles) and adenosine triphosphate (ATP; filled circles) from each of the four drug‐containing microelectrodes on a single microchip over a period of several days. SSA was released at − 1.0 V; ATP was released at − 0.8 V. (Reprinted with permission from Ref 51. Copyright 2009 Elsevier).

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Metallurgical microscope image of the part of a microchip exhibiting four polypyrrole (PPy) microelectrodes doped by sulfosalicylic acid (SSA) and one doped by adenosine triphosphate (ATP). Reprinted from Ge D, Tian X, Qi R, Huang S, Mu J, et al. A polypyrrole‐based microchip for controlled drug release. (Reprinted with permission from Ref 51. Copyright 2009 Elsevier).

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HPLC analysis of released vasopressin from the implantable rapid drug delivery device. With kind permission from Springer Science + Business Media: Elman NM, Ho Duc HL, Cima MJ. An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care. (Reprinted with permission from Ref 21. Copyright 2009 Springer Science + Business Media).

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Raghava, S, Goel, G, Kompella, UB. Chapter 22, Ophthalmic applications of nanotechnology. Pp 413‐435 in Tombran‐Tink, J, Barnstable, CJ, eds., Ocular transporters in ophthalmic diseases and drug delivery. Totowa, NJ: Humana Press; 2008.
Wang, PP, Frazier, J, Brem, H. Local drug delivery to the brain. Adv Drug Deliv Rev 2002, 16:987–1013.
FDA (Home, Office of Combination Products): http://www.fda.gov/oc/combination/
MicroCHIPS (Home): http://www.mchips.com/
Debiotech, SA: http://www.debiotech.com/home/index.html (Home) http://www.debiotech.com/products/msys/insulinpump.html (Insulin Nanopump^TM)

Resources

Further Reading

Books

Papazoglou, ES, Parthasarathy, A. BioNanotechnology. Synthesis Lectures on Biomedical Engineering 2007, 2:1-139. doi: 10.2200/S00051ED1V01Y200610BME007.
Saliterman SS. Fundamentals of BioMEMS and medical microdevices. Bellingham, WA: SPIE Press; 2006.

Articles

Selected Surveys and Introductions to Aspects of MEMS-based Technology

Jain, KK. Chapter 1, Drug delivery systems overview. Pp 1-50 in Jain, KK, ed., Methods in Molecular Biology, Vol. 437: Drug Delivery Systems. Totowa, NJ: Humana Press; 2008. doi:10.1007/978-1-59745-210-6_1.
James, T, Mannoor, MS, Ivanov, DV. Review: BioMEMS –advancing the frontiers of medicine. Sensors 2008, 8:6077-6107.
Kumar, R. The emerging therapy of tomorrow with nanomedicine: present status. Internet J Neural 2008, 10(1)[no page numbers].

Selected Overviews, Specific Applications of MEMS-based Therapies

Biondi, M, Ungaro, F, Quaglia, F, Netti, PA. Controlled drug delivery in tissue engineering. Adv Drug Deliv Rev 2008, 60:229-242. doi:10.1016/j.addr.2007.08.038.
Elder JB, Hoh DJ, Oh BC, Heller AC, Liu CY, Apuzzo ML. The future of cerebral surgery: a kaleidoscope of opportunities. Neurosurgery 2008, 62:1555-79; discussion 1579-82. doi: 10.1227/01.NEU.0000316426.13241.A9
Farokhzad OC, Dimitrakov JD, Karp JM, Khademhosseini A, Freeman MR, Langer R. Drug delivery systems in urology-getting “smarter”. Urology 2006, 68:463-9. doi:10.1016/j.urology.2006.03.069.
Moldovan, NI, Ferrari, M. Prospects for microtechnology and nanotechnology in bioengineering of replacement microvessels. Arch Pathol Lab Med 2002, 126:320-4.
Raghava, S, Goel, G, and Kompella, UB. Chapter 22, Ophthalmic applications of nanotechnology. Pp 413-435 in Tombran-Tink, J, Barnstable, CJ, eds., Ocular transporters in ophthalmic diseases and drug delivery. Totowa, NJ: Humana Press; 2008.
Wang, PP, Frazier, J, Brem H. Local drug delivery to the brain. Adv Drug Deliv Rev 2002, 16:987-1013.

Websites

FDA (Home, Office of Combination Products): http://www.fda.gov/oc/combination/
MicroCHIPS (Home): http://www.mchips.com/
Debiotech S.A.:
http://www.debiotech.com/home/index.html (Home)
http://www.debiotech.com/products/msys/insulinpump.html (Insulin Nanopump^TM)

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