2012 Biocompatibele MEMS / Microsystems Packaging
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This presentaion is a short introduction into the fascinating subject of biocompatible packaging of MEMS / micro systems. I gave this presentation for a technology cluster of Dutch micro systems companies
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2012 Biocompatibele MEMS / Microsystems Packaging
- 1. Biocompatibility of MEMS Packaging Materials Capita Selecta for MEMS Packaging TC Jan Eite Bullema
- 2. Content Jan Eite Bullema Biocompatible Packaging 2 What is Biocompatibility? Typical Biocompatible Materials Tests / Specifications for Biocompatibility Examples of Bio MEMS devices Biocompatibility of MEMS materials Conclusion
- 3. ‘Biocompatibility’ Jan Eite Bullema Biocompatible Packaging 3 According to The Williams dictionary of Bio Materials “Biocompatibility: The ability of a material to perform with an appropriate host response in a specific application”
- 4. ‘Biocompatibility’ Jan Eite Bullema Biocompatible Packaging 4 ‘Biocompatibility’ generally means to have no toxic or adverse effect on a living organism, or to a subset of that organism, such as cells, tissue, etc... Something that is biocompatible will not trigger an immune response (leading to rejection) if it is placed in or on a living organism. The term ‘biocompatible’ may refer to a specific material, or more generally, to an entire device. Since the objective of Bio-MEMS devices is function within the body (in-vivo), or to analyze living tissue/cells (in-vitro), it is important to ensure that any portion of the device that is in contact with the body/cells is ‘biocompatible’.
- 5. Consequence Not Biocompatible Jan Eite Bullema Biocompatible Packaging 5 If a material is used that is not biocompatible there may be complications such as: • Extended chronic inflammation at the contact point or where leachates interact with the body • Generation of materials that are toxic to cells (cytotoxicity) • Cell disruption • Skin irritation • Restenosis (narrowing of blood vessels after treatment) • Thrombosis (formation of blood clots) • Corrosion of an implant (if used) Lack of biocompatibility can result in disruption of the normal healing processes and additional complications Biocompatibility is vital for medical devices. 2005 Zeus Industrial Products
- 6. Biocompatibility The possession of both of two essential properties; (1) the lack of toxicity and (2) effective function. This may be the most misused term in biomaterials research when used to describe a material. Biocompatibility is not a property of a material. Jones, Biomaterials, artificial organs and tissue engineering
- 7. Content Jan Eite Bullema Biocompatible Packaging 8 What is Biocompatibility? Typical Biocompatible Materials Tests / Specifications for Biocompatibility Examples of Bio MEMS devices Biocompatibility of MEMS materials Conclusion
- 8. Biocompatible Materials Market Volume in US 2,7 x 109 USD in 2010 Synthetic Polymers 52% Natural Polymers 22% Metals 16% Ceramics 10% Jan Eite Bullema Biocompatible Packaging 9 www.freedoniagroup.com
- 9. Titanium • Joint replacement systems • Dental implants • Fusion cages • Trauma fixation devices • Pacemaker and defibrillator cases • Cochlear implant houses • Stents • Mechanical heart valves Jan Eite Bullema Biocompatible Packaging 10
- 10. Biocompatible Polymers Polymers that are biocompatible, i.e. those that are not toxic to the body on implantation, can be classified as being bioinert or bioresorbable. Generally, high molecular weight biocompatible polymers are non-degradable and are classed as bioinert. Toxicity can occur with normally biocompatible polymers due to leaching of low molecular weight plasticizers and additives. It is important to characterize the grade of polymer in use. Titel van de presentatie 11 Jones, Biomaterials, artificial organs and tissue engineering
- 11. Repeat units of polymers Titel van de presentatie 13 Jones, Biomaterials, artificial organs and tissue engineering
- 12. Biocompatible Polymers What is sold as polymer X by one manufacturer may be very different from polymer X sold by another, due to purity and additives present. Surface reactions and absorption of proteins at the polymer surface can also cause problems. Therefore, the surface texture and the shape of the implant are also important. Titel van de presentatie 14 Jones, Biomaterials, artificial organs and tissue engineering
- 13. Bioinert polymers Common non-degradable medical polymers include: polyethylene terephthalate (PET), nylon 6,6 polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene (PE, low density and high density and ultra-high molecular weight, UHMW), polysiloxanes (silicones) and poly(methylmethacrylate) (PMMA). It should be noted that there is some evidence of enzymatic degradation of PET, nylon and PU but the amount of degradation is generally very small, the exception being some types of polyurethanes Titel van de presentatie 15 Jones, Biomaterials, artificial organs and tissue engineering
- 14. Poly(methylmethacrylate) / PMMA Poly(methylmethacrylate) is a hard rigid, glassy but brittle, polymer with a glass transition temperature of about 100 °C It is classified as bioinert In set forms it is used as intraocular lenses and hard contact lenses. In situ setting forms (known as cold curing) are used as bone cements in joint replacement surgery Titel van de presentatie 16 Jones, Biomaterials, artificial organs and tissue engineering
- 15. Poly(tetrafluoroethylene) (PTFE) PTFE has the chemical structure [–CF2–CF2]n. It is chemically extremely stable and is a classic example of a bioinert polymer. It must be noted that all commercial PTFEs only approximate to the chemical composition given above. PTFE is highly crystalline and the crystallites have a high melting point (330 °C), which makes PTFE difficult to process It cannot be moulded to shape. Particles are sintered then machined to the required form. The commercial material Gortex® is a fibrous sheet form of PTFE that has numerous uses as a membrane material PTFE has relatively poor mechanical properties with a low yield strength Titel van de presentatie 17 Jones, Biomaterials, artificial organs and tissue engineering
- 16. Polyethylene Polyethylene has the chemical structure [–CH2–CH2]n. Three types are used in biomedical applications: • low density polyethylene LDPE (lower degree of crystallinity); • high density polyethylene HDPE (higher degree of crystallinity); • ultra-high molecular weight polyethylene UHMWPE (molar mass > 106) LDPE and HDPE are readily mouldable. UHMWPE is not, and, like PTFE, is sintered and machined to shape. Polyethylene, like PTFE, is a hydrophobic (water-repellent) and bioinert polymer Titel van de presentatie 18 Jones, Biomaterials, artificial organs and tissue engineering
- 17. Polysiloxanes (silicones) Polysiloxanes are widely used for medical applications and have a long success record. Material types include elastomers, gels, lubricants, foams and adhesives. Polysiloxanes are: - very chemically stable and unreactive. - very hydrophobic and have a low moisture uptake. - good electrical insulation characteristics Polysiloxanes are the polymer of choice for long-term use in the body where an elastomer is required and where there is a demand for biodurability and biocompatibility . Titel van de presentatie 19 Jones, Biomaterials, artificial organs and tissue engineering
- 18. Polyurethanes Polyurethanes are polymers that contain the urethane group. A large number of urethane polymers exist with widely different physical and biological properties. The urethane grouping can be considered as resulting from the reaction of an isocyanate and an alcohol. Chain extension may be performed by glycols or diamines. The nature of e chain extender is very important in that it determines chain flexibility. Most polyurethanes for medical use are two-phase block copolymers (also termed segmented polyurethanes). Titel van de presentatie 25 Jones, Biomaterials, artificial organs and tissue engineering
- 19. Bioresorbable polymers A bioresorbable polymer is designed to degrade within the body after performing its function. Useful materials often degrade to give normal metabolites of the body. Examples include: polylactide, polyglycolide, poly(-3-hydroxybutyrate), polyhyaluronic acid esters, polydioxanone and copolymers of the above, plus additional species such as poly(glycolic acid/lactic acid) and poly(glycolide-trimethylene carbonate). Biodegradable/hydrolysable polymers are frequently the basis of scaffolds for tissue engineering. Tissue engineering is growth of tissue in vitro, often by seeding cells on a template (scaffold) that can guide the tissue growth Titel van de presentatie 27 Jones, Biomaterials, artificial organs and tissue engineering
- 20. Hydrogels Hydrogels are insoluble water-swollen networks that are being investigated for biomedical applications such as drug delivery and tissue engineering. These polymers consist of a wide range of chemistries. Titel van de presentatie 28 Jones, Biomaterials, artificial organs and tissue engineering
- 21. Content Jan Eite Bullema Biocompatible Packaging 31 What is Biocompatibility? Typical Biocompatible Materials Tests / Specifications for Biocompatibility Examples of Bio MEMS devices Biocompatibility of MEMS materials Conclusion
- 22. ISO 10993 / EN 30993: Biological Evaluation of Medical Devices Medical devices sold in the EU must comply with the EU Medical Devices Directive 93/42/EEC. This specifies the safety assessment requirements to ensure that patients are not exposed to unnecessary risks. The Directive uses the safety assessments of ISO 10993/EN 30993 (Biological Evaluation of Medical Devices) as a method to define the testing required for devices that are directly or indirectly in contact with the body or bodily fluids. Compliance with the Directive is necessary to achieve CE marking of products for sale inside the EU. Jan Eite Bullema Biocompatible Packaging 32
- 23. ISO 10993 / EN 30993: Biological Evaluation of Medical Devices Jan Eite Bullema Biocompatible Packaging 34 Surface Devices Externally Communicating Devices Implant Devices 2005 Zeus Industrial Products
- 24. Differences between FDA and EU regulations The FDA’s primary role, as established by the Congress of the USA in regulating medical devices, is protecting the public health. Everything beyond that is secondary to the FDA’s mission. In the EU system of regulation there is an emphasis on the importance of a standardised ‘internal market’ as well as protecting public health. Titel van de presentatie 36 Jones, Biomaterials, artificial organs and tissue engineering
- 25. Differences between FDA and EU regulations Another difference between the USA and EU systems is that the FDA individually reviews every device that is submitted to it and determines whether that device may be marketed. A company may not put a device on the market in the USA until, in some manner, they have notified the FDA. For Class 2 and Class 3 devices, FDA must approve the device before the company is allowed to sell the device. Titel van de presentatie 37 Jones, Biomaterials, artificial organs and tissue engineering
- 26. Material Characterization Assessment of biocompatibility requires good material characterization. Material characterization should be used to the extent that it is possible to positively identify the material being used. This is of particular importance with plastics where nominally similar grades may contain varying amounts and types of plasticizers, stabilizers and fillers. These additives are critical in biocompatibility, and not only the type but the amount of additives must be positively identified. This information is critical in leaching studies where leachates can be toxic or lead to biocompatibility concerns. Jan Eite Bullema Biocompatible Packaging 41 2005 Zeus Industrial Products
- 27. Proposal for a compact implantable packaging Jan Eite Bullema Biocompatible Packaging 45 IMAPS 2011, Maaike Op de Beeck (1) all chips are individually encapsulated by diffusion barriers using a wafer level process (2) biocompatible chip interconnect and embedding of multiple chips (3) final system assembly including biocompatible metallization and final embedding
- 28. Test protocol for cytotoxicity tests To investigate the biocompatibility of the material, cytotoxicity tests are performed based on the ISO10993-5 standard. A thin layer (~100nm) of the barrier material is deposited on a blanket silicon wafer and diced into 4x4cm squares for testing. After cleaning, a glass ring is glued on the surface with biocompatible PDMS to define the cell culture area Jan Eite Bullema Biocompatible Packaging 46 Cell-culture-dish-like test structure with the layer under test as bottom of cell culture dish IMAPS 2011, Maaike Op de Beeck
- 29. Viability Hippocampal cells after treatment with a ‘Live/Dead cell assay’ : cells are stained with fluorescent dyes: the green dye colors the healthy cells, and dead cells are colored by a red dye. Jan Eite Bullema Biocompatible Packaging 47 IMAPS 2011, Maaike Op de Beeck
- 30. Viability A high viability means that cells can proliferate well on the material under test The cell viability of the negative control, a standard cell culture dish, should be very high (otherwise the test is considered false and has to be repeated), and all cell viabilities of the test are compared with the negative control. We consider a material non-cytotoxic if the cell viability is not deviating more than 10% from the negative control, which should have a viability of at least 75%. Jan Eite Bullema Biocompatible Packaging 48 IMAPS 2011, Maaike Op de Beeck
- 31. Test protocol diffusion tests of the barrier layers Cu is chosen as test vehicle since it is commonly present in chips and since it is known to diffuse fast. Furthermore, Cu diffusion into a cell culture will be detected easy since Cu is (highly) toxic for most cells. Cu is etched by most cell culture media, hence biofluid diffusion through the barrier layer will cause etching of the underlying Cu patterns. Jan Eite Bullema Biocompatible Packaging 49 IMAPS 2011, Maaike Op de Beeck
- 32. Test protocol for cytotoxicity tests and diffusion barrier tests Jan Eite Bullema Biocompatible Packaging 50 IMAPS 2011, Maaike Op de Beeck
- 33. Typical Tests Results Diffusion Barrier Properties Jan Eite Bullema Biocompatible Packaging 51 Obtained cell viabilities using various types of cells after co-culture on conductive barriers. Cardiomyocytes are most sensitive to Cu diffusion IMAPS 2011, Maaike Op de Beeck
- 34. Typical Tests Results Diffusion Barrier Properties Jan Eite Bullema Biocompatible Packaging 52 Cadiomyocytes viability after co-culture tests on insulating barrier materials. C- is the negative control or cell culture reference. IMAPS 2011, Maaike Op de Beeck
- 35. Content Jan Eite Bullema Biocompatible Packaging 53 What is Biocompatibility? Typical Biocompatible Materials Tests / Specifications for Biocompatibility Examples of Bio MEMS devices Biocompatibility of MEMS materials Conclusion
- 36. MEMS Technology for Physiologically Integrated Devices Implantable MEMS - Bio Sensors - Stents - Immuno Isolation - Drug Delivery - Micro particles - Micro reservoir in silicon / Micro reservoirs in polymer Injectable MEMS - Micro Needles - Injectable Micro Modules Jan Eite Bullema Biocompatible Packaging 54 PROCEEDINGS OF THE IEEE, VOL. 92, NO. 1, JANUARY 2004
- 37. Fully Integrated Biochip Platforms Jan Eite Bullema Biocompatible Packaging 55 Sensors 2012, 12, 11013-11060
- 38. Implantable Glucose Sensor. Biocompatible PEEK Jan Eite Bullema Biocompatible Packaging 56
- 39. Glaucoma Drainage Device with Parylene Coating Jan Eite Bullema Biocompatible Packaging 57 Implantable Parylene MEMS for Glaucoma Therapy
- 40. Biocompatible BenzoCycloButene (BCB) Jan Eite Bullema Biocompatible Packaging 58 Biosensors and Bioelectronics 20 (2004) 404–407
- 41. Polyimide-based peripheral nerve electrode coated with Silicon Carbide Jan Eite Bullema Biocompatible Packaging 59 Optical photograph of a polyimide-based peripheral nerve electrode coated with a thin a-SiC film
- 42. Content Jan Eite Bullema Biocompatible Packaging 60 What is Biocompatibility? Typical Biocompatible Materials Tests / Specifications for Biocompatibility Examples of Bio MEMS devices Biocompatibility of MEMS materials Conclusion
- 43. Biocompatible MEMS Materials Typical materials that are considered as ‘biocompatible’, and have been used in micro-fabrication of MEMS devices include: - Many polymers , e.g. PMMA (acrylic) Parylene - Metals, e.g. Gold, Titanium - Some ceramics: Silicon nitride and silicon carbide Other common MEMS materials are not bio-compatible. - Glass is appropriate for in-vitro, but not in-vivo. - Silicon requires surface treatment for in-vitro, and is also not compatible for in-vivo applications. Jan Eite Bullema Biocompatible Packaging 62
- 44. Biocompatibility and Bio fouling of MEMS Jan Eite Bullema Biocompatible Packaging 63 Reduced Biofouling Gold Silicon nitride Silicon dioxide SU-8TM The in vivo inflammatory and wound healing response of MEMS drug delivery component materials were evaluated using the cage implant system. Materials, placed into stainless-steel cages, were implanted subcutaneously in a rodent model. Biocompatible Gold Silicon nitride Silicon dioxide SU-8TM Silicon Biomaterials 24 (2003) 1959–1967
- 45. Content Jan Eite Bullema Biocompatible Packaging 64 What is Biocompatibility? Typical Biocompatible Materials Tests / Specifications for Biocompatibility Examples of Bio MEMS devices Biocompatibility of MEMS materials Conclusion
- 46. Conclusion Biocompatibility testing of implant materials is becoming increasingly complex, and MEMS devices have unique biocompatibility issues. The ISO 10 993 standards outline minimum tests of material characterization, toxicity, and biodegradation that may be augmented depending on actual device usage. The biocompatibility requirements vary considerably depending on the device function and design. Jan Eite Bullema Biocompatible Packaging 65 PROCEEDINGS OF THE IEEE, VOL. 92, NO. 1, JANUARY 2004
- 47. Conclusion Biocompatibility can be assessed using several types of tests. In vitro assays include leaching of material, corrosion testing, protein adsorption testing, and cell culturing on material samples. In vivo biocompatibility assays typically involve the implantation of material or a device at the eventual site of use (intramuscular, subcutaneous, etc.) In vitro assays are easier to perform and provide more quantitative results, but in vivo assays are more relevant and can capture systemic effects Jan Eite Bullema Biocompatible Packaging 66 PROCEEDINGS OF THE IEEE, VOL. 92, NO. 1, JANUARY 2004
Editor's Notes
- Titanium to provide best prospects among metals Precious metals will sustain the largest demand value among biocompatible metals based on high price and widespread use in dental repair and restoration products. However, reflecting advantages of high strength, low modulus and strong body fluid resistance, titanium and titanium alloys will provide the best growth opportunities. These metals will extend applications in joint replacement systems; dental implants; fusion cages; trauma fixation devices; pacemaker and defibrillator cases; cochlear implant houses; stents; and mechanical heart valves. The penetration of titanium and titanium alloys into new and existing uses will weaken the growth potential of stainless steel and other biocompatible metals, such as cobalt chromium alloys
- A study by Jockisch, in 1992, showed that carbon fibre-reinforced poly-ether-ether-ketone (PEEK) has good mechanical properties. The fibrous capsule thickness around carbon-reinforced PEEK was smaller than unreinforced ultra high molecular weight polyethylene, indicating less micromovement of the carbon/PEEK device. Toxicology screening showed the device to have some debris present but this did not cause any major foreign body reaction. This type of fracture fixation plate has been used clinically but generally found not to be as reliable or biocompatible as metallic plates.
- All of the materials detailed in the previous sections have been used with resorbable α-polyester matrices. The two principal polymers used are poly(glycolic acid), PGA, poly(lactic acid), PLA, and co-polymers of the two (see Chapter 10). Polylactic acid degrades to produce non-toxic lactic acid, which is metabolised to carbon dioxide and water, and is easily excreted. The advantage of these polymers is that they have time-varying mechanical properties; resorption rate is reduced by increasing the volume fraction of PGA. Additions of randomly orientated chopped carbon fibre have shown to have improved mechanical properties to that of the pure polymer, but strengths
- However, whilst polyethylene is classified as bioinert, UHMWPE particles in the submicrometre size range arising from wear of acetabular cups are very toxic and cause bone necrosis and osteolytic lesions
- Nearly all polysiloxanes are based on polymethylsiloxane Polymethylsiloxane is rarely used without modification
- The polyester or polyether glycol forms the soft segment and matrix phase.
- Hydrogels are formed from both small (monomers) and large (macromers) precursors through a variety of reactions. Additionally, hydrogels consist of homopolymers (one monomer), copolymers (more than one monomer), and semi-interpenetrating networks, where one monomer is polymerised throughout an already cross-linked network. By altering the type of hydrogel, various physical properties can be altered and molecules can be introduced that control the hydrogel’s interactions with cells and tissues. Hydrogels are insoluble water-swollen networks that are being widely investigated for biomedical applications such as drug delivery and tissue engineering. They can be formed through a variety of mechanisms including physical and chemical gelation. Properties of hydrogels that are important to their design and use as biomaterials include swelling, mechanics and degradation. There have been many types of hydrogels developed for biomaterials applications. These hydrogels are either natural, e.g. fibrin, collagen and gelatin, hyaluronic acid, alginate and agarose or modified natural polymers or are synthetically derived, e.g. poly(ethylene glycol), poly(acrylic acid), poly(vinyl alcohol) and polypeptides. Many of these hydrogels are
- Every year, organ loss due to trauma or disease results in significant patient morbidity for millions of patients. While the gold standard for organ replacement is transplantation from both autologous and allogenic tissue sources, donor site morbidity (autologous) and donor shortage (allogenic) remain severe limitations. The field of tissue engineering offers great promise in the engineering of new tissue or organs using a number of different strategies
- The first stage of ISO 10993 is material characterization. If the material and use are the same as a device that has been historically safe, then biological evaluation may not be required and unnecessary testing can be avoided. For new materials and uses ISO 10993 provides a methodology for choosing a biological evaluation test program. The test program chosen depends on the ISO 10993 device category. This is based on the material used, the device category and the contact regime. In each category the length of contact is also important in setting the test program. Limited contact is regarded as less than 24 hours, prolonged contact is between 24 hours and 30 days, and permanent contact is greater than 30 days. The device categories and examples are given in Table 2 (below).
- Once the device category, contact regime, and contact timescale have been determined, ISO 10993 suggests the required biological testing for biocompatibility validation. ISO 10993 is not a formal checklist but a guide to the typical information requirements of approval authorities that can be used to design a testing program.
- The tests are: • Systemic Injection Test (intravenous and intraperitoneal) • Intracutaneous Test • Implantation Test The tests are classification based (Classes I to VI) from the responses to various specified extracts, materials, and routes of administration. The systemic injection test and the intracutaneous test use extracts prepared at one of three standard temperature/time regimes: 50°C for 72 hours, 70°C for 24 hours or 121°C (250°F) for 1hour.
- By contrast, in the EU system, the company submits its data and information to the notified body, which is a private organisation chartered through the EU. That notified body has the ability then to grant or issue the conformity mark – the CE mark – and the company is allowed to put its medical device into the market place. Under this scheme individual governments do not review the decision of the notified body. In the EU scheme, the notified body is given the authority to clear, or to allow, the medical devices to be sold.
- By contrast, in the EU system, the company submits its data and information to the notified body, which is a private organisation chartered through the EU. That notified body has the ability then to grant or issue the conformity mark – the CE mark – and the company is allowed to put its medical device into the market place. Under this scheme individual governments do not review the decision of the notified body. In the EU scheme, the notified body is given the authority to clear, or to allow, the medical devices to be sold.
- Medical devices are regulated by various authorities • USA – Food and Drug Administration (FDA) • UK – Medical Devices Agency • Japan – Ministry of Health and Welfare • European Union – CE Marking
- It was a risk assessment analysis that resulted in these 40 items. These 40 essential requirements can be broken down into six major classifications: 1. Internal production control: that is, elements where a company must perform certain tasks to ensure control over their production. 2. The essential elements specify the type of examination that a notified body can carry out to ensure that a company is manufacturing and designing medical devices according to the regulations. 3. It establishes how one can assess that a device conforms to its intended use and needs. 4. It lays out guidelines for quality assurance (QA) systems in production that must be followed. 5. It specifies how to verify that the product is doing what it was designed to do. 6. It specifies guidelines for how a company will pursue a company-wide quality assurance system.
- It was a risk assessment analysis that resulted in these 40 items. These 40 essential requirements can be broken down into six major classifications: 1. Internal production control: that is, elements where a company must perform certain tasks to ensure control over their production. 2. The essential elements specify the type of examination that a notified body can carry out to ensure that a company is manufacturing and designing medical devices according to the regulations. 3. It establishes how one can assess that a device conforms to its intended use and needs. 4. It lays out guidelines for quality assurance (QA) systems in production that must be followed. 5. It specifies how to verify that the product is doing what it was designed to do. 6. It specifies guidelines for how a company will pursue a company-wide quality assurance system.
- proposal for a compact implantable packaging (1) all chips are individually encapsulated by diffusion barriers using a wafer level process; (2) biocompatible chip interconnect and embedding of multiple chips by a supporting flexible polymer such as polyimide; (3) final system assembly including biocompatible metallization and final embedding, preferably in a soft biomimetic polymer.
- For co-culture tests, the material under test is covered with a suitable cell culture fluid and with healthy cells. The test culture is incubated for several days (37°C). In case harmful products will diffuse into the cell culture medium, cells will be harmed or even killed. After incubation, cells are stained by fluorescent dyes to enable a distinction between healthy and dead cells. Based on counting of the healthy and dead cells (or on fluorescence measurements) the cell viability is determined.
- A high viability means that cells can proliferate well on the material under test. For these kind of tests, always a double reference test is included, a positive and a negative control. The cell viability of the negative control, a standard cell culture dish, should be very high (otherwise the test is considered false and has to be repeated), and all cell viabilities of the test are compared with the negative control. We consider a material non-cytotoxic if the cell viability is not deviating more than 10% from the negative control, which should have a viability of at least 75%. Following the USP standard, up to 20% decrease from the control is still considered as non-cytotoxic, although we consider a viability decrease >10% as unacceptable, since we aim for long term implantation.
- An example of such a Cu etch by cell culture medium is shown. A Si wafer covered with 100nm of Cu is submersed in a common cell culture medium (Dulbecco’s Modified Eagle Medium (DMEM) with 5% FBS) for 5 hours. SEM evaluations before and after submersion proved that all Cu is etched. Also, the cell culture medium Two types of tests are needed for diffusion characterisation of barrier layers: (1) test of diffusion of Cu through the barrier layer, done by Cu sensitive cell cultures and (2) evaluation of fluid leaching through the barrier layer, done by Cu corrosion tests during/after submersion.
- A variety of implantable electronic devices are based upon or use MEMS technology, including sensors, immunoisolation capsules, and drug delivery microchips. These topics, as well as a novel application of microfabrication technology to stents, are briefly reviewed here. Long-term in vivo sensing is a critical component of the ideal closed-loop drug delivery or monitoring system, but the issue of implant biocompatibility and biofouling must be addressed in order to achieve long-term in vivo sensing. Although it is important to avoid adverse tissue responses to any implant, the degree of biocompatibility must be greater for a sensor. Sensing strategies for biosensors include optical [35], mechanical [36], magnetic [37], and electrochemical [38], [39] detection methods, as well as combinations of the above. For example, both optical and electrochemical sensors have been developed to monitor local pH in brain tissue and in blood [40], [41]. A multiparameter sensor has been reported that combines electrochemical and fiber-optic technology for continuous in vivo measurement of pH, carbon dioxide partial pressure, oxygen partial pressure, and oxygen saturation early in human pregnancy [42]. These examples illustrate how certain features of MEMS, in this case their ability to operate in both an optical and electrochemical manner, can be leveraged for broad utility. Microfabricated pressure sensors also have the potential for in vivo application.
- Abstract: Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications. According to the Molecular Diagnostics Survey Reports [1], diagnostics testing influences approximately 70% of health care decisions. This means that diagnostics are essential tools for diagnosing and managing numerous health care conditions, ranging from infectious diseases to non-communicable diseases such as diabetes. In fact, non-communicable diseases, or NCDs, are by far the leading cause of death in the world, representing 63% (36 million) of all annual deaths [2].
- An implantable glaucoma management system is presented for the first time. Glaucoma is an incurable disease characterized by gradual visual field loss that eventually results in blindness. Studies indicate that reduction of intraocular pressure reduces the rate of disease progress. A passive parylene MEMS pressure sensor and drainage shunt comprise a complete system for the detection and alleviation of elevated intraocular pressure. Tissue anchors for securing the pressure sensor to the iris have been developed to facilitate direct and convenient optical monitoring of intraocular pressure. Keywords – Glaucoma, glaucoma drainage devices, intraocular pressure sensor, parylene, tissue anchors CURRENT GLAUCOMA DRAINAGE DEVICES All modern GDDs are based on the 1969 concept of the Molteno implant which consists of tube that shunts aqueous humor from anterior chamber to an external subconjunctival plate [5] . In the last 30-40 years, very few innovative advances in surgical operation or implant devices have occurred. Only two major modifications to GDDs have been introduced: (1) addition of a valve to resist outflow and reduce hypotony and (2) increase in the endplate surface area to achieve lower IOPs. GDDs are currently limited to the treatment of refractory glaucoma due to complications. The most significant complication of GDDs is postoperative hypotony (a condition where IOP is abnormally low, IOP <5 mmHg) [6]. During the early postoperative period, there is a lack of flow resistance prior to fibrous capsule formation around the end-plate resulting in hypotony, flat anterior chambers, choroidal effusions, and suprachoroidal hemorrhages. Strategies to avoid hypotony include performing the operation in two-stages to allow fibrous capsule formation, tube ligature, internal tube occlusion, and the development of valved GDDs. These solutions are not ideal and interestingly, current valved implants do not perform as advertised and do not eliminate the occurrence of these complications. Furthermore, the success rate of current GDDs decreases by 10-15% every year suggesting poor long term performance [2]. To the best of our knowledge, no one has fabricated a complete GDD or a passive IOP sensor using MEMS technology. MEMS technology offers several advantages over traditional approaches to glaucoma therapy including highly functional microfluidic systems that can be adapted to drug delivery and IOP management; miniaturized sensors suitable for implantation with precise and accurate readouts [7]; precision and batch fabrication. The purpose of a GDD is to control and regulate IOP, however, current GDDs are lacking in function and in efficacy. These factors are partly attributed to suboptimal design and nonideal biomaterial selection. By leveraging polymer MEMS technology, all the components necessary for a GDD can be seamlessly integrated into a miniaturized, single-piece device that is biocompatible and minimizes complications. Our MEMS GDD is an implantable, passive parylene shunt to reduce and regulate IOP by controlling the removal of excess aqueous humor from the anterior chamber. GDDs must be designed to incorporate several physiological parameters. Aqueous humor is produced in the eye at 2.4±0.6 μL/min (mean±SD) and changes over the course of a day (morning: 3.0 μL/min; afternoon: 2.4 μL/min; evening: 1.5 μL/min). The resistance of conventional AH drainage tissues is ~3-4 mmHg/μL/min [3]. The minimal system requirements for a MEMS GDD are a shunt and pressure-sensitive valve to remove excess AH such that IOP is maintained between 5-22 mmHg. A parylene shunt has been fabricated using a sacrificial silicon technology. A shunt mold is etched into a silicon wafer and parylene is deposited around the mold. Each shunt is removed from the master mold and the silicon is chemically removed. In Fig. 1, several types of shunts are shown with one end sealed off (~8×0.5×1 mm3 and 10 μm thick wall). At the sealed-ends, remnants of the silicon mold are visible. This closed end is implanted into the anterior chamber of the eye where it comes into contact with AH. At this end of the shunt are several regions where the parylene has been etched down to 0.5 μm or less. When elevated IOP is detected these thinned regions can be
- Before insertion into brain, the fabricated electrode should meet a strict biocompatibility standard. Our electrodes are composed of BCB, gold, silicon, and parylene-C. The cell adhesion behavior of a completed electrode exposed to monolayers of 3T3 fibroblasts (ATCC #CRL-6476) cell line in vitro was studied using a Live/Dead Viability/Cytotoxicity Kit (L-3224, Molecular Probes) and previously described methods (Trudel and Massia, 2002). The morphology of 3T3 cells showed conformal coverage over all the surfaces and was similar to cells cultured on tissue culture plastic. Thus, the completed electrode was considered a non-toxic substrate for cell adhesion and cell growth.
- The biocompatibility and biofouling of the microfabrication materials for a MEMS drug delivery device have been evaluated. The in vivo inflammatory and wound healing response of MEMS drug delivery component materials, metallic gold, silicon nitride, silicon dioxide, silicon, and SU-8TM photoresist, were evaluated using the cage implant system. Materials, placed into stainless-steel cages, were implanted subcutaneously in a rodent model. Exudates within the cage were sampled at 4, 7, 14, and 21 days, representative of the stages of the inflammatory response, and leukocyte concentrations (leukocytes/ml) were measured. Overall, the inflammatory responses elicited by these materials were not significantly different than those for the empty cage controls over the duration of the study. The material surface cell density (macrophages or foreign body giant cells, FBGCs), an indicator of in vivo biofouling, was determined by scanning electron microscopy of materials explanted at 4, 7, 14, and 21 days. The adherent cellular density of gold, silicon nitride, silicon dioxide, and SU-8TM were comparable and statistically less (po0:05) than silicon. These analyses identified the MEMS component materials, gold, silicon nitride, silicon dioxide, SU-8TM, and silicon as biocompatible, with gold, silicon nitride, silicon dioxide, and SU-8TM showing reduced biofouling.
- The performance of sensors (glucose, pH, etc.), for example, is limited by biofouling and isolation of the sensor surface. However, neural electrodes must remain in intimate contact with the neurons that they are stimulating or recording.
- In vitro assays are easier to perform and provide more quantitative results, but in vivo assays are more relevant and can capture systemic effects. The local and systemic responses, such as fibrous capsule formation, lymphocyte response, or accumulation of particulates in lymph nodes, are evaluated over days, weeks, or months. In vivo tests can also exhibit variation due to implant shape, surface texture, and size. Large implants, sharp edges, and implants that rub against tissue will induce a greater reaction in the host tissue. The variability of test design mirrors the variability of device function. The biocompatibility of MEMS materials was not addressed until recently because these materials were packaged or encapsulated away from direct contact with tissue and fluids; biocompatibility is a surface-mediated property, and the biocompatibility of a device depends only on those materials in contact with tissue. The biocompatibility of silicon and other MEMS materials has become much more important with the advent of implantable MEMS devices that interact directly with the body. The biocompatibility of some MEMS electrode materials has been studied, however, because of their use in other devices such as pacemaker electrodes and dental implants.