Drug-releasing implants: current progress, challenges and perspectives.

The need for more efficient drug delivery strategies to treat resilient diseases and the rise of micro and nanotechnology have led to the development of more sophisticated drug-releasing implants with improved capabilities and performances for localised and controlled therapies. In recent years, implantable drug-releasing systems have emerged as an outstanding alternative to conventional clinical therapies. This new breed of implants has shown promising capabilities to overcome the inherent problems of conventional implants and therapies, making clinical treatments more efficient with minimal side effects. Recent clinical trials have demonstrated that this technology can improve the life of patients and increase their life expectancy. Within this context, this review is aimed at highlighting the different types and concepts of drug-releasing implants incorporating new nanomaterials and nanotechnology-based devices. Furthermore, the principles on which these drug-releasing implants are based as well as their advantages and limitations are discussed in detail. Finally, we provide a future perspective in the development of implantable clinical drug-delivery systems based on micro and nanotechnology.

[1]  Deepak Chitkara,et al.  Biodegradable injectable in situ depot-forming drug delivery systems. , 2006, Macromolecular bioscience.

[2]  J. Addai-Mensah,et al.  A multi-drug delivery system with sequential release using titania nanotube arrays. , 2012, Chemical communications.

[3]  Feasibility, safety, and efficacy of a novel polymeric pimecrolimus-eluting stent: traditional pre-clinical safety end points failed to predict 6-month clinical angiographic results. , 2009, JACC. Cardiovascular interventions.

[4]  Shiqiao Qin,et al.  Fabrication of pH-sensitive graphene oxide–drug supramolecular hydrogels as controlled release systems , 2012 .

[5]  Göran Stemme,et al.  Side-opened out-of-plane microneedles for microfluidic transdermal liquid transfer , 2003 .

[6]  Michael J Sailor,et al.  Biodegradable luminescent porous silicon nanoparticles for in vivo applications. , 2009, Nature materials.

[7]  Volker Lehmann,et al.  Electrochemistry of Silicon: Instrumentation, Science, Materials and Applications , 2002 .

[8]  Daniel G Anderson,et al.  Injectable nano-network for glucose-mediated insulin delivery. , 2013, ACS nano.

[9]  T. Kosmač,et al.  Rapid biomimetic deposition of octacalcium phosphate coatings on zirconia ceramics (Y-TZP) for dental implant applications , 2012 .

[10]  Dusan Losic,et al.  Controlled drug release from porous materials by plasma polymer deposition. , 2010, Chemical communications.

[11]  Hideki Masuda,et al.  Self-Ordering of Cell Configuration of Anodic Porous Alumina with Large-Size Pores in Phosphoric Acid Solution , 1998 .

[12]  E. Hunziker,et al.  Osteoinductive Implants: The Mise-en-scène for Drug-Bearing Biomimetic Coatings , 2004, Annals of Biomedical Engineering.

[13]  Vesa-Pekka Lehto,et al.  Fabrication and chemical surface modification of mesoporous silicon for biomedical applications , 2008 .

[14]  Philipp Beerbaum,et al.  Long-term biocompatibility of a corrodible peripheral iron stent in the porcine descending aorta. , 2006, Biomaterials.

[15]  P. Heasman,et al.  Local delivery of chlorhexidine gluconate (PerioChipTM) in periodontal maintenance patients , 2001 .

[16]  Michael J Sailor,et al.  Reflective interferometric fourier transform spectroscopy: a self-compensating label-free immunosensor using double-layers of porous SiO2. , 2006, Journal of the American Chemical Society.

[17]  D. Ma,et al.  In situ gelation and sustained release of an antitumor drug by graphene oxide nanosheets , 2012 .

[18]  M. Madou,et al.  Microactuators toward microvalves for responsive controlled drug delivery , 2000 .

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

[20]  M. Enayati,et al.  In-vitro/In-vivo comparison of leuprolide acetate release from an in-situ forming plga system , 2013, DARU Journal of Pharmaceutical Sciences.

[21]  Dusan Losic,et al.  Local drug delivery to the bone by drug-releasing implants: perspectives of nano-engineered titania nanotube arrays. , 2012, Therapeutic delivery.

[22]  S. Gehrke,et al.  Enhanced loading and activity retention of bioactive proteins in hydrogel delivery systems. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[23]  S. Nyman,et al.  Healing of Bone Defects by Guided Tissue Regeneration , 1988, Plastic and reconstructive surgery.

[24]  B. K. Davis Diffusion of polymer gel implants. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Robert Langer,et al.  In vivo delivery of BCNU from a MEMS device to a tumor model. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[26]  P. Zambelli,et al.  Orthopedic implant used as drug delivery system: clinical situation and state of the research. , 2008, Current Drug Delivery.

[27]  Nicolas H Voelcker,et al.  The biocompatibility of porous silicon in tissues of the eye. , 2009, Biomaterials.

[28]  M. Sailor,et al.  Engineering the chemistry and nanostructure of porous silicon Fabry-Pérot films for loading and release of a steroid. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[29]  Arti Vashist,et al.  Recent advances in hydrogel based drug delivery systems for the human body. , 2014, Journal of materials chemistry. B.

[30]  Tae-Sung Bae,et al.  Enhanced biocompatibility of a pre-calcified nanotubular TiO2 layer on Ti–6Al–7Nb alloy , 2013 .

[31]  K. Puri,et al.  Local drug delivery agents as adjuncts to endodontic and periodontal therapy , 2013, Journal of medicine and life.

[32]  Robert C Eberhart,et al.  The influence of thermal treatment on the mechanical characteristics of a PLLA coiled stent. , 2008, Journal of biomedical materials research. Part B, Applied biomaterials.

[33]  Christopher E. Nelson,et al.  Tunable Delivery of siRNA from a Biodegradable Scaffold to Promote Angiogenesis In Vivo , 2014, Advanced materials.

[34]  P. Dubey,et al.  Composite polymer-bioceramic scaffolds with drug delivery capability for bone tissue engineering , 2013, Expert opinion on drug delivery.

[35]  Mark R. Prausnitz,et al.  Dissolving Polymer Microneedle Patches for Influenza Vaccination , 2010, Nature Medicine.

[36]  Michael J Sailor,et al.  Biosensing using porous silicon double-layer interferometers: reflective interferometric Fourier transform spectroscopy. , 2005, Journal of the American Chemical Society.

[37]  S. Bauer,et al.  Bioactivation of titanium surfaces using coatings of TiO(2) nanotubes rapidly pre-loaded with synthetic hydroxyapatite. , 2009, Acta biomaterialia.

[38]  Dusan Losic,et al.  Real-time and in situ drug release monitoring from nanoporous implants under dynamic flow conditions by reflectometric interference spectroscopy. , 2013, ACS applied materials & interfaces.

[39]  A. Ayón,et al.  Drug loading of nanoporous TiO2 films , 2006, Biomedical materials.

[40]  M. Staples,et al.  Dosage Form Development, in Vitro Release Kinetics, and in Vitro–in Vivo Correlation for Leuprolide Released from an Implantable Multi-reservoir Array , 2007, Pharmaceutical Research.

[41]  T. Hanawa Materials for metallic stents , 2009, Journal of Artificial Organs.

[42]  Patrik Schmuki,et al.  Influence of Water Content on the Growth of Anodic TiO2 Nanotubes in Fluoride-Containing Ethylene Glycol Electrolytes , 2010 .

[43]  N M Elman,et al.  An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care , 2009, Biomedical microdevices.

[44]  R W Bucholz,et al.  The pathological anatomy of Malgaigne fracture-dislocations of the pelvis. , 1981, The Journal of bone and joint surgery. American volume.

[45]  R. Virmani,et al.  Particle debris from a nanoporous stent coating obscures potential antiproliferative effects of tacrolimus‐eluting stents in a porcine model of restenosis , 2005, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[46]  Nicolas H Voelcker,et al.  Evaluation of mammalian cell adhesion on surface-modified porous silicon. , 2006, Biomaterials.

[47]  Dusan Losic,et al.  Porous alumina with shaped pore geometries and complex pore architectures fabricated by cyclic anodization. , 2009, Small.

[48]  Zhipeng Hou,et al.  Photoactivated Composite Biomaterial for Soft Tissue Restoration in Rodents and in Humans , 2011, Science Translational Medicine.

[49]  Patrick W Serruys,et al.  Monitoring in vivo absorption of a drug-eluting bioabsorbable stent with intravascular ultrasound-derived parameters a feasibility study. , 2010, JACC. Cardiovascular interventions.

[50]  Jens Wolf,et al.  Pharmakafreisetzende biodegradierbare Polymerbeschichtung von dentalen Titanimplantaten zur Verbesserung der Weichgewebsintegration / Drug release of coated dental implant neck region to improve tissue integration , 2009, Biomedizinische Technik. Biomedical engineering.

[51]  Craig A. Grimes,et al.  Anodic Growth of Highly Ordered TiO2 Nanotube Arrays to 134 μm in Length , 2006 .

[52]  Tejal A Desai,et al.  Fabrication and evaluation of nanoporous alumina membranes for osteoblast culture. , 2005, Journal of biomedical materials research. Part A.

[53]  H. Ohgushi,et al.  Efficacy of slow-releasing anticancer drug delivery systems on transplantable osteosarcomas in rats. , 1995, Japanese Journal of Clinical Oncology.

[54]  Dusan Losic,et al.  Biocompatible polymer coating of titania nanotube arrays for improved drug elution and osteoblast adhesion. , 2012, Acta biomaterialia.

[55]  Sungho Jin,et al.  Stem cell fate dictated solely by altered nanotube dimension , 2009, Proceedings of the National Academy of Sciences.

[56]  John T Santini,et al.  Electrothermally activated microchips for implantable drug delivery and biosensing. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[57]  W. Saltzman,et al.  Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. , 1998, Cancer research.

[58]  O. Terasaki,et al.  Ordered Mesoporous Microspheres for Bone Grafting and Drug Delivery , 2009 .

[59]  Henry Brem,et al.  Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[60]  Michael J Cima,et al.  Electronic MEMS for triggered delivery. , 2004, Advanced drug delivery reviews.

[61]  Tejal A Desai,et al.  Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nanotubes. , 2007, Biomaterials.

[62]  B D Boyan,et al.  Role of material surfaces in regulating bone and cartilage cell response. , 1996, Biomaterials.

[63]  David Cebon,et al.  Biocompatibility: Meeting a Key Functional Requirement of Next-Generation Medical Devices , 2008, Toxicologic pathology.

[64]  Fung,et al.  Polymeric implants for cancer chemotherapy. , 1997, Advanced drug delivery reviews.

[65]  Lei Gao,et al.  In situ gel-forming system: an attractive alternative for nasal drug delivery. , 2013, Critical reviews in therapeutic drug carrier systems.

[66]  Cisplatin-loaded porous Si microparticles capped by electroless deposition of platinum. , 2011, Small.

[67]  Tejal A Desai,et al.  Influence of engineered titania nanotubular surfaces on bone cells. , 2007, Biomaterials.

[68]  H. Santos,et al.  Amine modification of thermally carbonized porous silicon with silane coupling chemistry. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[69]  Fritz B Prinz,et al.  Biodegradable micro-osmotic pump for long-term and controlled release of basic fibroblast growth factor. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[70]  Patrik Schmuki,et al.  TiO2 nanotubes: synthesis and applications. , 2011, Angewandte Chemie.

[71]  J M Anderson,et al.  Issues and perspectives on the biocompatibility and immunotoxicity evaluation of implanted controlled release systems. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[72]  Jan M. Macak,et al.  Anodic growth of self-organized anodic TiO2 nanotubes in viscous electrolytes , 2006 .

[73]  Robert Langer,et al.  Multi-pulse drug delivery from a resorbable polymeric microchip device , 2003, Nature materials.

[74]  A. Boudier,et al.  PLGA in situ implants formed by phase inversion: critical physicochemical parameters to modulate drug release. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[75]  A. Sapelkin,et al.  Interaction of B50 rat hippocampal cells with stain-etched porous silicon. , 2006, Biomaterials.

[76]  Byung-Soo Kim,et al.  Effect of cross-linking reagents for hyaluronic acid hydrogel dermal fillers on tissue augmentation and regeneration. , 2010, Bioconjugate chemistry.

[77]  Q. Wei,et al.  The Effect of Carbon Nanotubes added into Bullfrog Collagen Hydrogel on Gentamicin Sulphate Release: In Vitro , 2011 .

[78]  Esther Eljarrat-Binstock,et al.  New Techniques for Drug Delivery to the Posterior Eye Segment , 2010, Pharmaceutical Research.

[79]  G. Whitford The Physiological and Toxicological Characteristics of Fluoride , 1990, Journal of dental research.

[80]  Guoqiang Jiang,et al.  PEG-g-chitosan thermosensitive hydrogel for implant drug delivery: cytotoxicity, in vivo degradation and drug release , 2014, Journal of biomaterials science. Polymer edition.

[81]  P. Schmuki,et al.  Mechanical properties of anatase and semi-metallic TiO2 nanotubes , 2010 .

[82]  D. Liepmann,et al.  Arrays of hollow out-of-plane microneedles for drug delivery , 2005, Journal of Microelectromechanical Systems.

[83]  Xiliang Luo,et al.  Carbon nanotube nanoreservior for controlled release of anti-inflammatory dexamethasone. , 2011, Biomaterials.

[84]  Galo Maldonado,et al.  1-year results of the hydroxyapatite polymer-free sirolimus-eluting stent for the treatment of single de novo coronary lesions: the VESTASYNC I trial. , 2009, JACC. Cardiovascular interventions.

[85]  A. McHugh,et al.  The role of polymer membrane formation in sustained release drug delivery systems. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[86]  J. Bumgardner,et al.  Chitosan Coatings Deliver Antimicrobials From Titanium Implants: A Preliminary Study , 2011, Implant dentistry.

[87]  M. Sailor Porous Silicon in Practice: Preparation, Characterization and Applications , 2012 .

[88]  W. Kao,et al.  Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems , 2010, Expert opinion on drug delivery.

[89]  M. Boman,et al.  Nanoporous aluminum oxide affects neutrophil behaviour , 2004, Microscopy research and technique.

[90]  Jonas Addai-Mensah,et al.  Magnetic-responsive delivery of drug-carriers using titania nanotube arrays , 2012 .

[91]  M Kellomäki,et al.  Drug-eluting bioabsorbable stents - an in vitro study. , 2009, Acta biomaterialia.

[92]  Zhuyin Sui,et al.  Easy and green synthesis of reduced graphite oxide-based hydrogels , 2011 .

[93]  Chaoliang He,et al.  In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[94]  M. Zilberman,et al.  Antibiotic-eluting medical devices for various applications. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[95]  P. Liu,et al.  TiO2 nanotubes as drug nanoreservoirs for the regulation of mobility and differentiation of mesenchymal stem cells. , 2012, Acta biomaterialia.

[96]  M. Kurisawa,et al.  Injectable biodegradable hydrogels: progress and challenges. , 2013, Journal of materials chemistry. B.

[97]  Motohiro Uo,et al.  Titania nanotubes supported gelatin stabilized gold nanoparticles for medical implants , 2011 .

[98]  H. Ince,et al.  Advances in coronary stent technology--active drug-loaded stent surfaces for prevention of restenosis and improvement of biocompatibility. , 2013, Current pharmaceutical biotechnology.

[99]  E. Fabrizio,et al.  Porous silicon as drug carrier for controlled delivery of doxorubicin anticancer agent , 2006 .

[100]  Raimund Erbel,et al.  Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, non-randomised multicentre trial , 2007, The Lancet.

[101]  M. Kellomäki,et al.  Biodegradable Self-Expanding Poly-L/D-Lactic Acid Vascular Stent: A Pilot Study in Canine and Porcine Iliac Arteries , 2004, Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists.

[102]  Thomas J. Webster,et al.  Anodized Ti and Ti 6 Al 4 V Possessing Nanometer Surface Features Enhances Osteoblast Adhesion , 2005 .

[103]  J. Macák,et al.  Formation of Double‐Walled TiO2 Nanotubes and Robust Anatase Membranes , 2008 .

[104]  H. Wen,et al.  Oral controlled release formulation design and drug delivery : theory to practice , 2010 .

[105]  Jeremy J Mao,et al.  Matrices and scaffolds for drug delivery in dental, oral and craniofacial tissue engineering. , 2007, Advanced drug delivery reviews.

[106]  N. Lang,et al.  Antimicrobial therapy using a local drug delivery system (Arestin) in the treatment of peri-implantitis. I: Microbiological outcomes. , 2006, Clinical oral implants research.

[107]  P. Yelick,et al.  Bioengineered Teeth from Cultured Rat Tooth Bud Cells , 2004, Journal of dental research.

[108]  H. Santos,et al.  ¹⁸F-labeled modified porous silicon particles for investigation of drug delivery carrier distribution in vivo with positron emission tomography. , 2011, Molecular pharmaceutics.

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

[110]  H. Nakajima,et al.  Titanium in Dentistry , 1996 .

[111]  M. Chiao,et al.  On-demand controlled release of docetaxel from a battery-less MEMS drug delivery device. , 2011, Lab on a chip.

[112]  Mauro Ferrari,et al.  Sustained small interfering RNA delivery by mesoporous silicon particles. , 2010, Cancer research.

[113]  Robert Langer,et al.  Application of Micro- and Nano-Electromechanical Devices to Drug Delivery , 2006, Pharmaceutical Research.

[114]  J. Bonnet,et al.  Tunable functionality and toxicity studies of titanium dioxide nanotube layers , 2010, 1004.0322.

[115]  Robert Gurny,et al.  Biodegradable polymers for the controlled release of ocular drugs , 1998 .

[116]  A. Uhlir Electrolytic shaping of germanium and silicon , 1956 .

[117]  Patrick W Serruys,et al.  A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods , 2009, The Lancet.

[118]  P. Tran,et al.  Opportunities for nanotechnology-enabled bioactive bone implants , 2009 .

[119]  F. Boey,et al.  Shape memory in un-cross-linked biodegradable polymers , 2008, Journal of biomaterials science. Polymer edition.

[120]  Nicholas Stowe,et al.  Quantification of in vivo doxorubicin transport from PLGA millirods in thermoablated rat livers. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[121]  L. Canham,et al.  Complete Tumor Response Following Intratumoral 32P BioSilicon on Human Hepatocellular and Pancreatic Carcinoma Xenografts in Nude Mice , 2005, Clinical Cancer Research.

[122]  D. Losic,et al.  Graphene and graphene oxide as new nanocarriers for drug delivery applications. , 2013, Acta biomaterialia.

[123]  L. Tang,et al.  Surface morphology and adsorbed proteins affect phagocyte responses to nano-porous alumina , 2006, Journal of materials science. Materials in medicine.

[124]  Kostas Kostarelos,et al.  Electroresponsive Polymer–Carbon Nanotube Hydrogel Hybrids for Pulsatile Drug Delivery In Vivo , 2013, Advanced healthcare materials.

[125]  K. Shakesheff,et al.  Adjuvant Chemotherapy for Brain Tumors Delivered via a Novel Intra-Cavity Moldable Polymer Matrix , 2013, PloS one.

[126]  Yahya E Choonara,et al.  A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases. , 2010, Journal of Pharmacy and Science.

[127]  L. Canham,et al.  Electronically-responsive delivery from a calcified mesoporous silicon structure , 2006, Biomedical microdevices.

[128]  Arben Merkoçi,et al.  Nanochannels preparation and application in biosensing. , 2012, ACS nano.

[129]  K. Gulati,et al.  Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating , 2011 .

[130]  Yuehe Lin,et al.  Graphene and graphene oxide: biofunctionalization and applications in biotechnology , 2011, Trends in Biotechnology.

[131]  M. Staples,et al.  Long-term Stability and in vitro Release of hPTH(1–34) from a Multi-reservoir Array , 2008, Pharmaceutical Research.

[132]  Go-Eun Kim,et al.  Bone regeneration around N-acetyl cysteine-loaded nanotube titanium dental implant in rat mandible. , 2013, Biomaterials.

[133]  W. Freeman,et al.  Intravitreal properties of porous silicon photonic crystals: a potential self-reporting intraocular drug-delivery vehicle , 2008, British Journal of Ophthalmology.

[134]  S. J. Lee,et al.  Biofunctional porous anodized titanium implants for enhanced bone regeneration. , 2014, Journal of biomedical materials research. Part A.

[135]  H. Spiegel,et al.  Cellular mechanisms of bone repair. , 1997, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[136]  K Kostarelos,et al.  Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. , 2009, Nature nanotechnology.

[137]  Robert Langer,et al.  Reservoir-based drug delivery systems utilizing microtechnology. , 2012, Advanced drug delivery reviews.

[138]  Melissa Ai Ling Teo,et al.  In Vitro and In Vivo Characterization of MEMS Microneedles , 2005, Biomedical microdevices.

[139]  T. Tohyama,et al.  [Treatment of malignant brain tumors with slowly releasing anticancer drug-polymer composites]. , 1986, No shinkei geka. Neurological surgery.

[140]  R. Erbel,et al.  Synergistic effects of a novel nanoporous stent coating and tacrolimus on intima proliferation in rabbits , 2003, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[141]  Giuseppe Benagiano,et al.  Contraceptive devices: subcutaneous delivery systems , 2008, Expert review of medical devices.

[142]  Abhishek Sahu,et al.  A stimuli-sensitive injectable graphene oxide composite hydrogel. , 2012, Chemical communications.

[143]  J. Folkman,et al.  THE USE OF SILICONE RUBBER AS A CARRIER FOR PROLONGED DRUG THERAPY. , 1964, The Journal of surgical research.

[144]  Rebecca S. Shawgo,et al.  BioMEMS for drug delivery , 2002 .

[145]  H. Yi,et al.  Gene Delivery of c-myb Increases Bone Formation Surrounding Oral Implants , 2013, Journal of dental research.

[146]  G. Lewis Alternative acrylic bone cement formulations for cemented arthroplasties: present status, key issues, and future prospects. , 2008, Journal of biomedical materials research. Part B, Applied biomaterials.

[147]  Mark R. Prausnitz,et al.  Suprachoroidal Drug Delivery to the Back of the Eye Using Hollow Microneedles , 2010, Pharmaceutical Research.

[148]  Young-Seak Lee,et al.  Electro-responsive transdermal drug delivery behavior of PVA/PAA/MWCNT nanofibers , 2011 .

[149]  B. Amsden,et al.  Solute Diffusion within Hydrogels. Mechanisms and Models , 1998 .

[150]  Henry Brem,et al.  Targeted therapy for brain tumours , 2004, Nature Reviews Drug Discovery.

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

[152]  D. Putnam,et al.  Engineering Polymer Systems for Improved Drug Delivery , 2013 .

[153]  G. Daculsi,et al.  Chemically Modified Calcium Phosphates as Novel Materials for Bisphosphonate Delivery , 2004 .

[154]  D. Quintanar-Guerrero,et al.  Preparation and characterization of triclosan nanoparticles for periodontal treatment. , 2005, International journal of pharmaceutics.

[155]  S. Bauer,et al.  Narrow window in nanoscale dependent activation of endothelial cell growth and differentiation on TiO2 nanotube surfaces. , 2009, Nano letters.

[156]  S. Lin,et al.  Tumoricidal effect of controlled-release polymeric needle devices containing adriamycin HCl in tumor-bearing mice. , 1989, Biomaterials, artificial cells, and artificial organs.

[157]  W. E. Brown,et al.  Effects of fluoride on enamel solubility and cariostasis. , 1977, Caries research.

[158]  Nicolas H Voelcker,et al.  Radiofrequency-triggered release for on-demand delivery of therapeutics from titania nanotube drug-eluting implants. , 2014, Nanomedicine.

[159]  Subbu Venkatraman,et al.  Collapse pressures of biodegradable stents. , 2003, Biomaterials.

[160]  Aldo R Boccaccini,et al.  A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics. , 2011, Biomaterials.

[161]  Viness Pillay,et al.  In Vitro, In Vivo, and In Silico Evaluation of the Bioresponsive Behavior of an Intelligent Intraocular Implant , 2013, Pharmaceutical Research.

[162]  Robert Langer,et al.  In vivo release from a drug delivery MEMS device. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[163]  M. Peuster,et al.  A novel approach to temporary stenting: degradable cardiovascular stents produced from corrodible metal—results 6–18 months after implantation into New Zealand white rabbits , 2001, Heart.

[164]  J. Addai-Mensah,et al.  Polymeric micelles in porous and nanotubular implants as a new system for extended delivery of poorly soluble drugs , 2011 .

[165]  Giuseppe Polimeni,et al.  Biology and principles of periodontal wound healing/regeneration. , 2006, Periodontology 2000.

[166]  A. Olivi,et al.  Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a New Approaches to Brain Tumor Therapy CNS Consortium trial. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[167]  H. Gu,et al.  Fabrication of a novel polymer-free nanostructured drug-eluting coating for cardiovascular stents. , 2013, ACS applied materials & interfaces.

[168]  M. Cristina Kenney,et al.  Intraocular Sustained-Release Delivery Systems for Triamcinolone Acetonide , 2009, Pharmaceutical Research.

[169]  J. Matriano,et al.  Macroflux® Microprojection Array Patch Technology: A New and Efficient Approach for Intracutaneous Immunization , 2004, Pharmaceutical Research.

[170]  J. Kinsella,et al.  Suitability of porous silicon microparticles for the long-term delivery of redox-active therapeutics. , 2011, Chemical communications.

[171]  Dusan Losic,et al.  Self-ordered nanopore and nanotube platforms for drug delivery applications , 2009, Expert opinion on drug delivery.

[172]  Abdelwahab Hassan,et al.  Spherical gelatin/CNTs hybrid microgels as electro-responsive drug delivery systems. , 2013, International journal of pharmaceutics.

[173]  Robert Langer,et al.  Molecular release from a polymeric microreservoir device: Influence of chemistry, polymer swelling, and loading on device performance. , 2004, Journal of biomedical materials research. Part A.

[174]  S. Piantadosi,et al.  The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: Phase I trial , 1995, Journal of Neuro-Oncology.

[175]  R. Kuroda,et al.  Interstitial chemotherapy with biodegradable ACNU pellet for glioblastoma. , 1994, Stereotactic and Functional Neurosurgery.

[176]  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.

[177]  H. Rack,et al.  Titanium alloys in total joint replacement--a materials science perspective. , 1998, Biomaterials.

[178]  T. Segura,et al.  Non-viral DNA delivery from porous hyaluronic acid hydrogels in mice. , 2014, Biomaterials.

[179]  M. Ferrari,et al.  Polycation-functionalized nanoporous silicon particles for gene silencing on breast cancer cells. , 2014, Biomaterials.

[180]  G. Holzapfel,et al.  Penetration-Enhanced Ultrasharp Microneedles and Prediction on Skin Interaction for Efficient Transdermal Drug Delivery , 2007, Journal of Microelectromechanical Systems.

[181]  G. Saidel,et al.  Drug-eluting polymer implants in cancer therapy , 2008 .

[182]  T. Thorson Phase behavior and stimuli response in lyotropic liquid crystalline templated photopolymers , 2013 .

[183]  P. van Damme,et al.  Safety and efficacy of a novel microneedle device for dose sparing intradermal influenza vaccination in healthy adults. , 2009, Vaccine.

[184]  J C Beck,et al.  Chronic (60-Week) Toxicity Study of DUROS Leuprolide Implants in Dogs , 2001, International journal of toxicology.

[185]  Xian Jun Loh,et al.  New biodegradable thermogelling copolymers having very low gelation concentrations. , 2007, Biomacromolecules.

[186]  D. Das,et al.  Permeability enhancement for transdermal delivery of large molecule using low-frequency sonophoresis combined with microneedles. , 2013, Journal of pharmaceutical sciences.

[187]  N. Voelcker,et al.  Evaluation of mesoporous silicon/polycaprolactone composites as ophthalmic implants. , 2010, Acta biomaterialia.

[188]  Peter Pivonka,et al.  Characterization of drug-release kinetics in trabecular bone from titania nanotube implants , 2012, International journal of nanomedicine.

[189]  Mauro Ferrari,et al.  Porous silicon advances in drug delivery and immunotherapy. , 2013, Current opinion in pharmacology.

[190]  Kostas Kostarelos,et al.  Design, engineering and structural integrity of electro-responsive carbon nanotube- based hydrogels for pulsatile drug release. , 2013, Journal of materials chemistry. B.

[191]  H. Singer,et al.  First biodegradable metal stent in a child with congenital heart disease: Evaluation of macro and histopathology , 2007, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[192]  Joseph G. Shapter,et al.  Self-ordering Electrochemistry: A Simple Approach for Engineering Nanopore and Nanotube Arrays for Emerging Applications* , 2011 .

[193]  S. Gronthos,et al.  Stem cells and future periodontal regeneration. , 2009, Periodontology 2000.

[194]  M. Cima,et al.  A controlled-release microchip , 1999, Nature.

[195]  R Langer,et al.  Microchips as Controlled Drug-Delivery Devices. , 2000, Angewandte Chemie.

[196]  Po-Ying Li,et al.  A passive MEMS drug delivery pump for treatment of ocular diseases , 2009, Biomedical microdevices.

[197]  Young-Seak Lee,et al.  The effect of carbon nanotubes on drug delivery in an electro-sensitive transdermal drug delivery system. , 2010, Biomaterials.

[198]  Tejal A Desai,et al.  Influence of nanoporous alumina membranes on long-term osteoblast response. , 2005, Biomaterials.

[199]  T. Desai,et al.  Osteogenic differentiation of marrow stromal cells cultured on nanoporous alumina surfaces. , 2007, Journal of biomedical materials research. Part A.

[200]  N. Roxhed,et al.  Membrane-sealed hollow microneedles and related administration schemes for transdermal drug delivery , 2008, Biomedical microdevices.

[201]  Thomas J Webster,et al.  Enhanced osteoblast adhesion to drug-coated anodized nanotubular titanium surfaces , 2008, International journal of nanomedicine.

[202]  Marc Aucouturier,et al.  Structure and physicochemistry of anodic oxide films on titanium and TA6V alloy , 1999 .

[203]  Robert Langer,et al.  Drugs on Target , 2001, Science.

[204]  M. Endo,et al.  Carbon nanotubes: biomaterial applications. , 2009, Chemical Society reviews.

[205]  R. Gonzalez,et al.  A nanostructured titania bioceramic implantable device capable of drug delivery to the temporal lobe of the brain , 2007 .

[206]  Seajin Oh,et al.  Dissolvable microneedle patches for the delivery of cell-culture-derived influenza vaccine antigens. , 2012, Journal of pharmaceutical sciences.

[207]  Robert Langer,et al.  A BioMEMS review: MEMS technology for physiologically integrated devices , 2004, Proceedings of the IEEE.

[208]  W. Freeman,et al.  Hydrosilylated porous silicon particles function as an intravitreal drug delivery system for daunorubicin. , 2013, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[209]  Peng Liu,et al.  Influence of the titania nanotubes dimensions on adsorption of collagen: an experimental and computational study. , 2014, Materials science & engineering. C, Materials for biological applications.

[210]  Mauro Ferrari,et al.  Tailored porous silicon microparticles: fabrication and properties. , 2010, Chemphyschem : a European journal of chemical physics and physical chemistry.

[211]  Jin Kon Kim,et al.  Electrically actuatable smart nanoporous membrane for pulsatile drug release. , 2011, Nano letters.

[212]  L. Canham Bioactive silicon structure fabrication through nanoetching techniques , 1995 .

[213]  S. Socransky,et al.  Long-term effect of surgical/non-surgical treatment of periodontal disease. , 1984, Journal of clinical periodontology.

[214]  W. Freeman,et al.  Real-time monitoring of sustained drug release using the optical properties of porous silicon photonic crystal particles. , 2011, Biomaterials.

[215]  P. Perugini,et al.  Investigation of the degradation behaviour of poly(ethylene glycol-co-d,l-lactide) copolymer , 2007 .

[216]  Meital Zilberman,et al.  Mechanical properties and in vitro degradation of bioresorbable fibers and expandable fiber-based stents. , 2005, Journal of biomedical materials research. Part B, Applied biomaterials.

[217]  Sachiko Ono,et al.  Self‐Ordering of Cell Arrangement of Anodic Porous Alumina Formed in Sulfuric Acid Solution , 1997 .

[218]  X. Mo,et al.  Hierarchically designed injectable hydrogel from oxidized dextran, amino gelatin and 4-arm poly(ethylene glycol)-acrylate for tissue engineering application , 2012 .

[219]  K. Fowers,et al.  OncoGel (ReGel/paclitaxel)--clinical applications for a novel paclitaxel delivery system. , 2009, Advanced drug delivery reviews.

[220]  Po-Ying Li,et al.  An electrochemical intraocular drug delivery device , 2008, 2007 IEEE 20th International Conference on Micro Electro Mechanical Systems (MEMS).

[221]  W. Freeman,et al.  Ocular silicon distribution and clearance following intravitreal injection of porous silicon microparticles. , 2013, Experimental eye research.

[222]  Dorian Liepmann,et al.  Clinical microneedle injection of methyl nicotinate: stratum corneum penetration , 2005, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[223]  J. L. Linton Quantitative measurements of remineralization of incipient caries. , 1996, American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics.

[224]  Changhua Liu,et al.  Controlled release of anticancer drug using graphene oxide as a drug-binding effector in konjac glucomannan/sodium alginate hydrogels. , 2014, Colloids and surfaces. B, Biointerfaces.

[225]  M. Helmus,et al.  Physical characterization of controlled release of paclitaxel from the TAXUS Express2 drug-eluting stent. , 2004, Journal of biomedical materials research. Part A.

[226]  P. Gupta,et al.  Hydrogels: from controlled release to pH-responsive drug delivery. , 2002, Drug discovery today.

[227]  O. Pillai,et al.  Polymers in drug delivery. , 2001, Current opinion in chemical biology.

[228]  Chun Li,et al.  A pH-sensitive graphene oxide composite hydrogel. , 2010, Chemical communications.

[229]  Hongwei Ni,et al.  Antibacterial nano-structured titania coating incorporated with silver nanoparticles. , 2011, Biomaterials.

[230]  N. Laperriere,et al.  Gliadel wafers in the treatment of malignant glioma: a systematic review , 2007, Current oncology.

[231]  W. Freeman,et al.  Oxidized porous silicon particles covalently grafted with daunorubicin as a sustained intraocular drug delivery system. , 2013, Investigative ophthalmology & visual science.

[232]  Lingzhou Zhao,et al.  Antibacterial coatings on titanium implants. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[233]  Nicanor I Moldovan,et al.  Delivery of antiangiogenic and antioxidant drugs of ophthalmic interest through a nanoporous inorganic filter. , 2004, Molecular vision.

[234]  Georg Nickenig,et al.  A novel paclitaxel-eluting stent with an ultrathin abluminal biodegradable polymer 9-month outcomes with the JACTAX HD stent. , 2010, JACC. Cardiovascular interventions.

[235]  J. Addai-Mensah,et al.  Polymer micelles for delayed release of therapeutics from drug-releasing surfaces with nanotubular structures. , 2012, Macromolecular bioscience.

[236]  Lay Poh Tan,et al.  Biodegradable stents with elastic memory. , 2006, Biomaterials.

[237]  Gianmario Schierano,et al.  Biological factors involved in the osseointegration of oral titanium implants with different surfaces: a pilot study in minipigs. , 2005, Journal of periodontology.

[238]  Tejal A Desai,et al.  Peptide-immobilized nanoporous alumina membranes for enhanced osteoblast adhesion. , 2005, Biomaterials.

[239]  Dusan Losic,et al.  Nanoporous anodic aluminium oxide: Advances in surface engineering and emerging applications , 2013 .

[240]  Peter Greil,et al.  Time-dependent growth of biomimetic apatite on anodic TiO2 nanotubes , 2008 .

[241]  P. Candeloro,et al.  Water soluble nanoporous nanoparticle for in vivo targeted drug delivery and controlled release in B cells tumor context. , 2010, Nanoscale.

[242]  Volker Lehmann,et al.  Electrochemistry of Silicon , 2002 .

[243]  Emeka Nkenke,et al.  In vivo evaluation of anodic TiO2 nanotubes: an experimental study in the pig. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[244]  S. Piantadosi,et al.  Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas , 1995, The Lancet.

[245]  G. Perale,et al.  Drug eluting sutures: a model for in vivo estimations. , 2012, International journal of pharmaceutics.

[246]  D. Hunkeler,et al.  Rationalizing the design of polymeric biomaterials. , 1999, Trends in biotechnology.

[247]  Mark G. Allen,et al.  Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[248]  C. Nienaber,et al.  Iliac Anastomotic Stenting with a Sirolimus-Eluting Biodegradable Poly-L-Lactide Stent: A Preliminary Study after 6 Weeks , 2006, Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists.

[249]  N. Holalkere,et al.  EUS-guided injection of paclitaxel (OncoGel) provides therapeutic drug concentrations in the porcine pancreas (with video). , 2006, Gastrointestinal endoscopy.

[250]  Kenji Fukuda,et al.  Ordered Metal Nanohole Arrays Made by a Two-Step Replication of Honeycomb Structures of Anodic Alumina , 1995, Science.

[251]  Arindam Giri,et al.  Polymer hydrogel from carboxymethyl guar gum and carbon nanotube for sustained trans-dermal release of diclofenac sodium. , 2011, International journal of biological macromolecules.

[252]  Mauro Ferrari,et al.  Tailoring width of microfabricated nanochannels to solute size can be used to control diffusion kinetics. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[253]  F. Ahmad,et al.  Recent approaches for the treatment of periodontitis. , 2008, Drug discovery today.

[254]  I. Rodríguez,et al.  Controlled Fabrication of Multitiered Three‐Dimensional Nanostructures in Porous Alumina , 2008 .

[255]  I. Thesleff,et al.  Developmental biology and building a tooth. , 2003, Quintessence international.

[256]  Ester Segal,et al.  Bombarding Cancer: Biolistic Delivery of therapeutics using Porous Si Carriers , 2013, Scientific Reports.

[257]  David P. Martin,et al.  Absorbable polymer stent technologies for vascular regeneration , 2009 .

[258]  Cun-Yu Wang,et al.  Mesenchymal Stem Cell-Mediated Functional Tooth Regeneration in Swine , 2006, PloS one.

[259]  Ralf B. Wehrspohn,et al.  Self-ordering Regimes of Porous Alumina: The 10% Porosity Rule , 2002 .

[260]  Pentti Tengvall,et al.  A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants , 2012, BDJ.

[261]  P. Costa,et al.  Modeling and comparison of dissolution profiles. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[262]  T. Kissel,et al.  In situ forming parenteral drug delivery systems: an overview. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[263]  John P Carr,et al.  DUROS® Technology Delivers Peptides and Proteins at Consistent Rate Continuously for 3 to 12 Months , 2008, Journal of diabetes science and technology.

[264]  V. Pillay,et al.  An in vitro study of the design and development of a novel doughnut-shaped minitablet for intraocular implantation. , 2006, International journal of pharmaceutics.

[265]  Kai Yang,et al.  Carbon materials for drug delivery & cancer therapy , 2011 .

[266]  P. Bishop Clinical Experiment in Oestrin Therapy , 1938, British medical journal.

[267]  John A Ormiston,et al.  First‐in‐human implantation of a fully bioabsorbable drug‐eluting stent: The BVS poly‐L‐lactic acid everolimus‐eluting coronary stent , 2007, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[268]  Dusan Losic,et al.  Non-eroding drug-releasing implants with ordered nanoporous and nanotubular structures: concepts for controlling drug release. , 2014, Biomaterials science.

[269]  A. Colombo,et al.  Biodegradable stents : "fulfilling the mission and stepping away". , 2000, Circulation.

[270]  C. Grimes,et al.  Controlled Molecular Release Using Nanoporous Alumina Capsules , 2003 .

[271]  Yan Jin,et al.  Periodontal tissue engineering and regeneration: current approaches and expanding opportunities. , 2010, Tissue engineering. Part B, Reviews.

[272]  L. Canham,et al.  Porosified Silicon Wafer Structures Impregnated With Platinum Anti-Tumor Compounds: Fabrication, Characterization, and Diffusion Studies , 2000 .

[273]  Andy H. Choi,et al.  Current Perspectives , 2013, Journal of dental research.

[274]  William H. Smyrl,et al.  Titanium Dioxide Nanotube Arrays Fabricated by Anodizing Processes Electrochemical Properties , 2006 .

[275]  Raimund Erbel,et al.  Drug-eluting bioabsorbable magnesium stent. , 2004, Journal of interventional cardiology.

[276]  Dusan Losic,et al.  Nanoengineered drug-releasing Ti wires as an alternative for local delivery of chemotherapeutics in the brain , 2012, International journal of nanomedicine.

[277]  Dusan Losic,et al.  Preparation of porous anodic alumina with periodically perforated pores. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[278]  Raimund Erbel,et al.  Early- and long-term intravascular ultrasound and angiographic findings after bioabsorbable magnesium stent implantation in human coronary arteries. , 2009, JACC. Cardiovascular interventions.

[279]  David Erickson,et al.  A robust, electrochemically driven microwell drug delivery system for controlled vasopressin release , 2009, Biomedical microdevices.

[280]  Gurminder Singh,et al.  Intraoral Fluoride-Releasing Devices: A Literature Review , 2012 .

[281]  R. Siegel,et al.  BioMEMS devices for drug delivery , 2009, IEEE Engineering in Medicine and Biology Magazine.

[282]  H. Santos,et al.  Drug permeation across intestinal epithelial cells using porous silicon nanoparticles. , 2011, Biomaterials.

[283]  Jaan Hong,et al.  Influence of nanoporesize on platelet adhesion and activation , 2008, Journal of materials science. Materials in medicine.

[284]  John T Santini,et al.  Chronic, programmed polypeptide delivery from an implanted, multireservoir microchip device , 2006, Nature Biotechnology.

[285]  Michael J. Sailor,et al.  Compatibility of Primary Hepatocytes with Oxidized Nanoporous Silicon , 2001 .

[286]  M. Ferrari,et al.  Discoidal Porous Silicon Particles: Fabrication and Biodistribution in Breast Cancer Bearing Mice , 2012, Advanced functional materials.

[287]  Lin Yu,et al.  Injectable block copolymer hydrogels for sustained release of a PEGylated drug. , 2008, International journal of pharmaceutics.

[288]  Regina Luttge,et al.  Silicon micromachined hollow microneedles for transdermal liquid transport , 2003 .