Pioneering medical advances through nanofluidic implantable technologies.

Nanofluidic implantables represent a recent advance in a broad effort for developing personalized, point-of-care medical technologies. Such systems have unprecedented potential when matched with the newest developments in robotics, microprocessing, and tissue engineering. In this review, we present their emergence in medicine within the fields of diagnostics, biosensing, therapeutics, and theranostics. Discussion includes current limitations and future directions for these systems, as commensurate advances in power density and electronic processing are continually redefining the possible. As the research and funding attention coincide with complementary technological breakthroughs, the field is expected to grow into an advanced toolset for preserving human health. WIREs Nanomed Nanobiotechnol 2017, 9:e1455. doi: 10.1002/wnan.1455.

[1]  Mauro Ferrari,et al.  Investigating Islet Immunoisolation Parameters Using Microfabricated Membranes , 1998 .

[2]  Shelley R. Winn,et al.  Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and parkinsonian symptoms , 1995, Experimental Neurology.

[3]  Robert Langer,et al.  Multi-reservoir device for detecting a soluble cancer biomarker. , 2007, Lab on a chip.

[4]  Mauro Ferrari,et al.  Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. , 2008, Nature nanotechnology.

[5]  Francesco Portaluppi,et al.  Role of sleep-wake cycle on blood pressure circadian rhythms and hypertension. , 2007, Sleep medicine.

[6]  John N. Staniforth,et al.  An Electrically Modulated Drug Delivery Device: I , 1991, Pharmaceutical Research.

[7]  Ieee Robotics MEMS 2001 : the 14th IEEE International Conference on Micro Electro Mechanical Systems : Interlaken, Switzerland, January 21-25, 2001 : technical digest , 2001 .

[8]  Silvia Ferrati,et al.  The nanochannel delivery system for constant testosterone replacement therapy. , 2015, The journal of sexual medicine.

[9]  Mohammad Atai,et al.  Nano-porous thermally sintered nano silica as novel fillers for dental composites. , 2012, Dental materials : official publication of the Academy of Dental Materials.

[10]  K K Jain,et al.  Recent Advances in Nanooncology , 2008, Technology in cancer research & treatment.

[11]  P. Wilshaw,et al.  Initial in vitro interaction of osteoblasts with nano-porous alumina. , 2003, Biomaterials.

[12]  F. Lim,et al.  Microencapsulated islets as bioartificial endocrine pancreas. , 1980, Science.

[13]  N. M. Contento,et al.  Recessed ring-disk nanoelectrode arrays integrated in nanofluidic structures for selective electrochemical detection. , 2013, Analytical chemistry.

[14]  Tejal A Desai,et al.  Polycaprolactone Thin-Film Micro- and Nanoporous Cell-Encapsulation Devices. , 2015, ACS nano.

[15]  Mauro Ferrari,et al.  Delivering Enhanced Testosterone Replacement Therapy through Nanochannels , 2015, Advanced healthcare materials.

[16]  J. Sweedler,et al.  Metabolic differentiation of neuronal phenotypes by single-cell capillary electrophoresis-electrospray ionization-mass spectrometry. , 2011, Analytical chemistry.

[17]  Yuzi Liu,et al.  Bottom-up, hard template and scalable approaches toward designing nanostructured Li2S for high performance lithium sulfur batteries. , 2015, Nanoscale.

[18]  Mauro Ferrari,et al.  A robust nanofluidic membrane with tunable zero-order release for implantable dose specific drug delivery. , 2010, Lab on a chip.

[19]  Wadih Arap,et al.  Vascular Targeting: Recent Advances and Therapeutic Perspectives , 2006, Trends in Cardiovascular Medicine.

[20]  C. Wilke,et al.  Correlation of diffusion coefficients in dilute solutions , 1955 .

[21]  Mauro Ferrari,et al.  Leveraging electrokinetics for the active control of dendritic fullerene-1 release across a nanochannel membrane. , 2015, Nanoscale.

[22]  Mauro Ferrari,et al.  Enabling individualized therapy through nanotechnology. , 2010, Pharmacological research.

[23]  Tejal A Desai,et al.  Nanoporous microsystems for islet cell replacement. , 2004, Advanced drug delivery reviews.

[24]  Mauro Ferrari,et al.  Characterization of nanochannel delivery membrane systems for the sustained release of resveratrol and atorvastatin: new perspectives on promoting heart health , 2013, Analytical and Bioanalytical Chemistry.

[25]  Tejal A Desai,et al.  Titania nanotubes: a novel platform for drug-eluting coatings for medical implants? , 2007, Small.

[26]  Mauro Ferrari,et al.  Sustained Zero‐Order Release of Intact Ultra‐Stable Drug‐Loaded Liposomes from an Implantable Nanochannel Delivery System , 2014, Advanced healthcare materials.

[27]  Craig A. Grimes,et al.  Crystallization and high-temperature structural stability of titanium oxide nanotube arrays , 2003 .

[28]  Lara Leoni,et al.  Biocompatibility of nanoporous alumina membranes for immunoisolation. , 2007, Biomaterials.

[29]  M Ferrari,et al.  Microfabricated immunoisolating biocapsules. , 1998, Biotechnology and bioengineering.

[30]  Hamid R. Djalilian,et al.  Efficacy of an osmotic pump delivered, GM-CSF-based tumor vaccine in the treatment of upper aerodigestive squamous cell carcinoma in rats , 2007, Cancer Immunology, Immunotherapy.

[31]  Silvia Ferrati,et al.  MP43-20 NANOTECHNOLOGY-BASED IMPLANT FOR LONG TERM TESTOSTERONE REPLACEMENT , 2014 .

[32]  Michaela Kendall,et al.  Long-term monitoring for nanomedicine implants and drugs. , 2016, Nature nanotechnology.

[33]  Ali Khademhosseini,et al.  Google Glass-Directed Monitoring and Control of Microfluidic Biosensors and Actuators , 2016, Scientific Reports.

[34]  Mauro Ferrari,et al.  Nanoengineered device for drug delivery application , 2004 .

[35]  G Orive,et al.  Long-term expression of erythropoietin from myoblasts immobilized in biocompatible and neovascularized microcapsules. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[36]  Mauro Ferrari,et al.  Device for rapid and agile measurement of diffusivity in micro- and nanochannels. , 2011, Analytical chemistry.

[37]  Francesco Portaluppi,et al.  Administration–time-dependent effects of blood pressure-lowering medications: basis for the chronotherapy of hypertension , 2010, Blood pressure monitoring.

[38]  Bharat Bhushan,et al.  Theory, fabrication and applications of microfluidic and nanofluidic biosensors , 2012, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[39]  Sanjay Garg,et al.  Osmotic pumps in drug delivery. , 2004, Critical reviews in therapeutic drug carrier systems.

[40]  Jeong-Seok Choi,et al.  Regeneration of Recurrent Laryngeal Nerve using Polycaprolactone (PCL) Nerve Guide Conduit Coated with Conductive Materials , 2015 .

[41]  Thomas Schubert,et al.  Cytological evaluation of the tissue-implant reaction associated with subcutaneous implantation of polymers coated with titaniumcarboxonitride in vivo. , 2004, Biomaterials.

[42]  Mauro Ferrari,et al.  Silicon nanotechnology for biofiltration and immunoisolated cell xenografts , 1995 .

[43]  Mauro Ferrari,et al.  Leveraging nanochannels for universal, zero-order drug delivery in vivo. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[44]  S. Takeuchi,et al.  Monodisperse Alginate Hydrogel Microbeads for Cell Encapsulation , 2007 .

[45]  Yeun-Ho Joung,et al.  Development of Implantable Medical Devices: From an Engineering Perspective , 2013, International neurourology journal.

[46]  Craig A. Grimes,et al.  Titanium oxide nanotube arrays prepared by anodic oxidation , 2001 .

[47]  Craig A. Grimes,et al.  A new benchmark for TiO2 nanotube array growth by anodization , 2007 .

[48]  C. Stevenson,et al.  An in vivo/in vitro comparison with a leuprolide osmotic implant for the treatment of prostate cancer. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[49]  A Grattoni,et al.  Nanochannel systems for personalized therapy and laboratory diagnostics. , 2010, Current pharmaceutical biotechnology.

[50]  Peter D. Jones,et al.  Can Nanofluidic Chemical Release Enable Fast, High Resolution Neurotransmitter-Based Neurostimulation? , 2016, Front. Neurosci..

[51]  Mauro Ferrari,et al.  Gated and near-surface diffusion of charged fullerenes in nanochannels. , 2011, ACS nano.

[52]  Mauro Ferrari,et al.  The Emerging Role of Nanotechnology in Cell and Organ Transplantation. , 2016, Transplantation.

[53]  P. Vos,et al.  Cell encapsulation: Promise and progress , 2003, Nature Medicine.

[54]  Patrick Tabeling,et al.  Monodisperse colloids synthesized with nanofluidic technology. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[55]  Eugeniu Balaur,et al.  Wetting behaviour of layers of TiO2 nanotubes with different diameters , 2005 .

[56]  M C Emre Simsekler,et al.  The regulation of mobile medical applications. , 2014, Lab on a chip.

[57]  Weng Tao,et al.  Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. , 2002, Investigative ophthalmology & visual science.

[58]  Richard W. Baker,et al.  Osmotic drug delivery : a review of the patent literature , 1995 .

[59]  Hyung Gyu Park,et al.  Ion exclusion by sub-2-nm carbon nanotube pores , 2008, Proceedings of the National Academy of Sciences.

[60]  R. Masel,et al.  The fabrication of all-silicon micro gas chromatography columns using gold diffusion eutectic bonding , 2009 .

[61]  Jiayang Song,et al.  An energy harvester from human vibrational kinetic energy for wearable biomedical devices , 2014 .

[62]  Craig A. Grimes,et al.  Highly-ordered TiO2 nanotube arrays up to 220 µm in length: use in water photoelectrolysis and dye-sensitized solar cells , 2007 .

[63]  R Lyle Hood,et al.  Nanochannel Implants for Minimally-Invasive Insertion and Intratumoral Delivery. , 2016, Journal of biomedical nanotechnology.

[64]  Gorka Orive,et al.  Xenogeneic transplantation of erythropoietin-secreting cells immobilized in microcapsules using transient immunosuppression. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[65]  Charles E. Rose,et al.  Factors Associated with Adherence and Concordance Between Measurement Strategies in an HIV Daily Oral Tenofovir/Emtricitibine as Pre-exposure Prophylaxis (Prep) Clinical Trial, Botswana, 2007–2010 , 2015, AIDS and Behavior.

[66]  Arturas Ziemys,et al.  Sustained Administration of Hormones Exploiting Nanoconfined Diffusion through Nanochannel Membranes , 2015, Materials.

[67]  Francesco Portaluppi,et al.  Circadian variation of blood pressure: the basis for the chronotherapy of hypertension. , 2007, Advanced drug delivery reviews.

[68]  A Tjellström,et al.  Electron microscopic observations on the soft tissue around clinical long-term percutaneous titanium implants. , 1995, Biomaterials.

[69]  D. Fisher,et al.  Pharmacokinetics of an Implanted Osmotic Pump Delivering Sufentanil for the Treatment of Chronic Pain , 2003, Anesthesiology.

[70]  Craig A. Grimes,et al.  The effect of electrolyte composition on the fabrication of self-organized titanium oxide nanotube arrays by anodic oxidation , 2005 .

[71]  Felix von Stetten,et al.  Microfluidic Apps for off-the-shelf instruments. , 2012, Lab on a chip.

[72]  Mathias Rommel,et al.  Simple and efficient method to fabricate nano cone arrays by FIB milling demonstrated on planar substrates and on protruded structures , 2012 .

[73]  P. V. van Riel,et al.  Adherence Rates and Associations with Nonadherence in Patients with Rheumatoid Arthritis Using Disease Modifying Antirheumatic Drugs , 2009, The Journal of Rheumatology.

[74]  Roland Zengerle,et al.  Alginate bead fabrication and encapsulation of living cells under centrifugally induced artificial gravity conditions , 2008 .

[75]  Jain Kk Future of nanomedicine: impact on healthcare & society. , 2015 .

[76]  Mauro Ferrari,et al.  Release of Biologically Functional Interferon-Alpha from a Nanochannel Delivery System , 2005, Biomedical microdevices.

[77]  Craig A Grimes,et al.  Enhanced photocleavage of water using titania nanotube arrays. , 2005, Nano letters.

[78]  Tejal A Desai,et al.  Nanoporous alumina capsules for cellular macroencapsulation: transport and biocompatibility. , 2005, Diabetes technology & therapeutics.

[79]  Giacomo Bruno,et al.  Impedance characterization, degradation, and in vitro biocompatibility for platinum electrodes on BioMEMS , 2015, Biomedical Microdevices.

[80]  G. Korbutt,et al.  Improved survival of microencapsulated islets during in vitro culture and enhanced metabolic function following transplantation , 2004, Diabetologia.

[81]  Juan G. Santiago,et al.  two-liquid electroosmotic pump using low applied voltage and power , 2010 .

[82]  Ali Mani,et al.  Electroosmotic pump performance is affected by concentration polarizations of both electrodes and pump. , 2011, Sensors and actuators. A, Physical.

[83]  P. Renaud,et al.  Ionic transport phenomena in nanofluidics: experimental and theoretical study of the exclusion-enrichment effect on a chip. , 2005, Nano letters.

[84]  Anna Demming,et al.  Nanotechnological selection , 2013, Nanotechnology.

[85]  R. Bisht,et al.  Chronomodulated drug delivery system: A comprehensive review on the recent advances in a new sub-discipline of ‘chronopharmaceutics’ , 2011 .

[86]  E. M. Renkin,et al.  FILTRATION, DIFFUSION, AND MOLECULAR SIEVING THROUGH POROUS CELLULOSE MEMBRANES , 1954, The Journal of general physiology.

[87]  Mauro Ferrari,et al.  Nanotechnologies and regenerative medical approaches for space and terrestrial medicine. , 2012, Aviation, space, and environmental medicine.

[88]  Tatsuya Kin,et al.  Indefinite islet protection from autoimmune destruction in nonobese diabetic mice by agarose microencapsulation without immunosuppression1 , 2003, Transplantation.

[89]  Mauro Ferrari,et al.  Characterization of a nanogland for the autotransplantation of human pancreatic islets. , 2013, Lab on a chip.

[90]  M. Ferrari,et al.  A low-voltage electrokinetic nanochannel drug delivery system. , 2011, Lab on a chip.

[91]  Won-Gun Koh,et al.  Micropatterning of a nanoporous alumina membrane with poly(ethylene glycol) hydrogel to create cellular micropatterns on nanotopographic substrates. , 2011, Acta biomaterialia.

[92]  Jörg P Kutter,et al.  Nanofluidic devices with two pores in series for resistive-pulse sensing of single virus capsids. , 2011, Analytical chemistry.

[93]  Alessandro Grattoni,et al.  Three-dimensional printed polymeric system to encapsulate human mesenchymal stem cells differentiated into islet-like insulin-producing aggregates for diabetes treatment , 2016, Journal of tissue engineering.

[94]  Jiahao Wu,et al.  Surface charge, electroosmotic flow and DNA extension in chemically modified thermoplastic nanoslits and nanochannels. , 2015, The Analyst.

[95]  Göran Stemme,et al.  A sub-micron particle filter in silicon , 1990 .

[96]  Asim Nisar,et al.  MEMS-based micropumps in drug delivery and biomedical applications , 2008 .

[97]  Mauro Ferrari,et al.  Validated RP-HPLC method for the simultaneous analysis of gemcitabine and LY-364947 in liposomal formulations. , 2013, Current drug targets.

[98]  Juan G. Santiago,et al.  A review of micropumps , 2004 .

[99]  Bernhard Wolfrum,et al.  Nanofluidic redox cycling amplification for the selective detection of catechol. , 2008, Analytical chemistry.

[100]  P. de Vos,et al.  Chemistry and biocompatibility of alginate-PLL capsules for immunoprotection of mammalian cells. , 2002, Journal of biomedical materials research.

[101]  Babak Ziaie,et al.  An Artificial Nano-Drainage Implant (ANDI) for Glaucoma Treatment , 2006, 2006 International Conference of the IEEE Engineering in Medicine and Biology Society.

[102]  Jongyoon Han,et al.  Concentration-enhanced rapid detection of human chorionic gonadotropin as a tumor marker using a nanofluidic preconcentrator , 2010 .

[103]  Fabian Kiessling,et al.  Passive versus active tumor targeting using RGD- and NGR-modified polymeric nanomedicines. , 2014, Nano letters.

[104]  Tunku Kamarul,et al.  A preliminary study comparing the use of allogenic chondrogenic pre‐differentiated and undifferentiated mesenchymal stem cells for the repair of full thickness articular cartilage defects in rabbits , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[105]  Shili Wang,et al.  Chromatographic separations in a nanocapillary under pressure-driven conditions. , 2008, Journal of chromatography. A.

[106]  Ali Mani,et al.  Theory and experiments of concentration polarization and ion focusing at microchannel and nanochannel interfaces. , 2010, Chemical Society reviews.