Bio-MEMS Technologies: Devices, Tissue Engineering, & Drug Delivery. Presentation by Stuart Cantor, Ph.D. on 2/4/16
Curator: Stuart Cantor, Ph.D.
OUTLINE:
• Introduction/Research
• Device Functions
• Micropumps, microneedles
• Sensors
• Regulatory
• Applications:Devices, Tissue Engineering, Drug Delivery
• Conclusions
What is Bio-MEMS?
It stands for Biological Micro-electro-mechanical Systems aka Lab-on-a-chip (LOC) or uTAS (micro total analysis systems) and these devices are considered to have at least one system dimension in the submicron or micron range (100 nm-200 µm).
Developed in 1985, Unipath commercialized “Clear Blue,” a pregnancy test still used today. This was the first microfluidic device containing paper and the first microfluidic product to market. It could precisely control rate and amount of drug delivery. Gonadotropin RH is most effective delivered in a pulsatile fashion to female patients as a treatment for infertility (Kuret, JA Goodman & Gilman, 1990, p.1334-1360). Currently there are 272 Bio MEMS/microfluidics companies:
SOURCE
http://fluidicmems.com/list-of-microfluidics-lab-on-a-chip-and-biomems-companies
Research:
Research using a Bio-MEMS device has shown that it can characterize differences between normal and malignant breast tissue. It integrates mechanical & electrical sensors to study change in electro-mechanical properties (via strain gauges) of tissue. A microindentation technique used to characterize mechanical properties.
Sensor array: 180 µm x 180 µm
Device size: 20 mm
Tissue: 1 mm, thickness 8 µm
Pandya, HJ. et al. Design and fabrication of a flexible MEMS-based electromechanical sensor array for breast cancer diagnosis. J. Micromech. Microeng. 2015; Jun 23; 25(7). pii: 075025.
There are a number of natural and synthetic biopolymers which can be used in Bio-MEMS devices:
• Gelatin
• PDMS: polydimethylsiloxane
• Alginate
• PLA: poly-L-lactic acid
• PLGA: poly(L-lactic-co-glycolic) acid
• PGS: poly(glycerol co-sebacate)
What are the Ideal Qualities of Biomaterials?
• Processed using mild conditions to facilitate protein or growth factor incorporation.
• Naturally promotes adhesion & normal function of seeded cells.
• Is biocompatible.
• Free from toxic solvent residues.
• Contains moieties for potential chemical surface modification.
• Exhibits slow & predictable degradation rates to maximize functional duration of the implanted device.
• Has robust yet flexible mechanical properties.
• Is relatively inexpensive.
Nano-scale devices are also being developed:
SOURCE
http://www.sciencedirect.com/science/article/pii/S0017931008002615
Kleinstreuer, C. Microfluidics of nano-drug delivery. Intl. J. Heat Mass Transf. (2008) 52:5590-5597.
Nanoparticles (NPs): Passive & Active Targeting
• Multi-functional nanoparticles (NPs) can extravasate thru tumor vessels & attach to cancer cells via passive & active targeting.
• Passive targeting: takes advantage of the leaky walls & poor lymphatic drainage of tumor vessels (enhanced permeability and retention).
• Active targeting can then enhance tumor accumulation via ligand-receptor binding. Incorporate ligands on drug’s surface to selectively attach to over-expressed antigens on receptors or tumor cells, also receptor-mediated endocytosis.
• NPs must come in close proximity to tumors. NPs with ~50nm diameters are most efficiently internalized by cells.
Device Components & Functions:
• Micropumps: mechanical & non-mechanical (no moving parts)
• Microneedles: Reduce Pain, $3 billion market for diabetic glucose self-testing.
• Functions:
sample preparation
purification
separation
reaction
transport
immobilization
sensors: detection of chemicals/biologics
quantification
Operational Issues:
At this scale precise fluid flow is critical as well as ensuring heat is properly dissipated in the device so that it does not overheat and short out the electrical components. Several operational issues exist for optimum performance:
• Liquid surface tension
• Micropump chamber design: influences volume stroke & pressure
• Molecular size (needs to be smaller than flow channels or needles)
• Heat dissipation
• Laminar fluid flow
• Very high surface area-to-volume ratio
• Reproducibility
• Some devices such as microneedles still in clinical trials:
3M™ Hollow Microstructured Transdermal System demonstrates a number of unique benefits, including reproducible intradermal delivery, delivering up to 2 mL of various viscosities and API-dependent Pharmacokinetic (PK) profiles.
SOURCE
Microneedles
• Silicon microneedles, pioneered by Kumetrix, are comparable in cross-section to a human hair, yet strong enough to penetrate human skin without breakage.
• Uses 200 nanoliter microcuvette to draw blood < 1 second.
• Kumetrix entered into agreement with Bayer diagnostics to develop its silicon micro-needle device.
Silicon Wafer Enlarged view of microneedles
SOURCE
http://microlab.berkeley.edu/text/seminars/slides/bioMEMS.pdf
Micropumps:
• Performance: flow rate, pressure generated, Reynolds # (fluid flow laminar (Re low) or turbulent, pump size
• Transdermal insulin delivery
• Anti-thrombogenic for blood transportation
• Injection of glucose for diabetics
• Administer neurotransmitters to neurons
• Electrochemical and ion conductive polymer film actuator pumps provide adequate flow rates at very low voltage.
• Micropumps based on piezoelectric actuation require higher voltage but have higher flow rates – used in drug delivery & biomedical applications
Sensors:
• Prussian Blue (Hexacyanoferrate)
Formula: Fe4[Fe(CN)6]3 • xH2O
SOURCE
https://en.wikipedia.org/wiki/Ferricyanide
• Wide use in biosensor field. Catalyzes H2O2 reduction-useful for oxidase enzyme-based assays.
• Can detect glucose, lactate, cholesterol, and galactose.
Foods: glutamate, alcohol, formate, lysine, oxalate.
• Prussian blue is an antidote (sequestering agent) for certain kinds of heacy metal poisoning (thallium and radioactive isotopes of cesium-137). In 2003, FDA approved Radiogardase, also known as Prussian blue, for the treatment of patients with known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium to increase their rates of elimination. Radiogardase is manufactured by HEYL Chemisch-pharmazeutische Fabrik GmbH & Co. KG.
Regulatory aspects:
There are three classifications of medical devices:
• Class I medical device: Does not present a potential for unreasonable risk of illness or injury. A MEMS device is air conduction hearing aides. MEMS microphones & speakers are used. When wireless tech. is added to these products, they become as Class II.
• Class II medical device: have moderate risk and require special controls (ex. post-market surveillance) in addition to general controls. Blood pressure monitoring is an example that uses a MEMS piezo-resistive pressure sensor to monitor B.P. and a MEMS accelerometer to sense arm position for a more accurate reading.
• Class III medical device: the most stringent & highest risk classification. Requires premarket approval (PMA). Examples using MEMS accelerometers are pacemakers and implantable cardioverter defibrillators to monitor heart activity. These devices present a potential, unreasonable risk of illness or injury. Most PMAs require clinical studies, only some 510(k) do.
• FDA has determined that general and special controls alone are insufficient to assure the safety and effectiveness of class III devices.
• FDA regulations provide 180 days to review the PMA and make a determination. In reality, the review time is normally longer.
• If there are 510(k)’s cleared by FDA and the new device is substantially equivalent to any of these cleared devices, then the applicant should submit a 510(k).
SOURCE
MEMS Journal, http://www.memsjournal.com/2012/11
Bio-MEMS devices have many applications
Leading companies and their applications:
• Abaxis: diagnostic POC blood analyzers
• Achira labs: LOC for immunoassays
• Biolithic: Point-of-Care (POC) infectious disease
• Cellanyx: cancer diagnosis
• Cellx: microfluidics for drug screening
• Debiotech: medical devices, blood glucose for diabetes
• Evotech: discovery/development of novel small molecule drugs
• Incept BioSystems: products for infertility
• MicroCHIPS: microchip, implantable drug delivery device- PTH delivery for osteoporosis (113 patents + 33 pending)
• Advancen- MOD® oral PCA device with RFID wristband provides healthcare facilities an improved way to manage pain at the bedside.
SOURCE
http://www.avancen.com/about_the_mod.php
• IONSYS – 2015, patient-controlled, fentanyl iontophoretic* transdermal system for post-op. pain mgmt. (approved in EU in 2006).
• Senseonics – Continuous glucose monitoring system.
*a technique of introducing ionic medicinal compounds into the body through the skin by applying a local electric current.
Senseonics Bio-MEMS device
SOURCE
• The miniaturized sensor is designed to measure glucose in the interstitial fluid for up to 90 days. Unlike current glucose sensors, this sensor is implanted SC on the upper arm.
• Encased in a biocompatible material, the sensor utilizes a unique fluorescent, glucose indicating polymer. A light emitting diode embedded in the sensor excites the polymer, and the polymer then rapidly signals changes in glucose concentration via a change in light output. The measurement is then relayed to the Transmitter.
• This entire measurement is designed to be done autonomously and independently without any prompting by the user.
Debiotech: device for Types 1 and 2 diabetes
JewelPUMPTM aMEMS integrated, ultra-precise, disposable pump-chip tech.
SOURCE
http://www.debiotech.com/newsite/page/index.php?page=product_01&id=1&id_prod=0
Already in large-scale production through partnership with ST Microelectronics.
A miniaturized Patch-pump with 500 Units of insulin for up to 7 days use.
The disposable unit is filled once and discarded entirely after use, while the controller unit (incl. the electronics) can be used for 2 years, making it the most cost effective and environmental friendly disposable pump for diabetes care
Ocular Drug Delivery
• 3 layers of PDMS and acrylic
• Ability to refill device once every 3 months (50-500 nL dosage)
• 10% phenylephrine (rapid pupil dilation in rabbits)
SOURCE
http://pubs.rsc.org/en/Content/ArticleLanding/2008/LC/b804690e#!divAbstract
Lo, R. et al. A refillable microfabricated drug delivery device for treatment of ocular diseases. Communication, Lab Chip (2008), 8:1027-1030.
Thin Film Pizeoelectric MEMS:
• Piezoelectricity is the linear coupling between polarization and an applied strain or stress. Piezoelectric materials generate electrical signals in response to applied mechanical stress.
• Major challenges have emerged as MEMS moves to smaller sizes and has increased integrated circuitry density while delivering fast response times.
• Scaling to NEMS requires revolutionary advances in actuators, sensors, and transducers. This will decrease the voltage burden on the integrated control electronics.
• Medical application: transducers for Ultrasound Medical Imaging
SOURCE
Eom, C-B and Trolier-McKinstry. Thin-film piezoelectric MEMS. Materials Research Society Bulletin. v. 37, Nov. 2012, p. 1007-1017.
HIV Monitoring
• Novel & cost-effective platform: integrates immuno-magnetic separation & cell enumeration.
• 10 µL whole blood processed to isolate CD4+ cells.
• PDMS plasma treatment (generates vey hydrophilic surface) allowed for accurate metering of CD4+ T-cell lysate. Interacts with silica-coated magnetic beads to form aggregates.
• Blood analysis within 24 hr. of draw gives best results.
• Accurate T-cell counts on par with flow cytometry (R2=0.98) over range from 106-2337 cells/µL.
Liu, Q et al. The ARTµS: a novel microfluidic CD4+ T-cell enumeration system for monitoring antiretroviral therapy in HIV patients. Lab Chip, 2016, Advance Article.
Microfluidic Devices from Silk Fibroin
• From Bombyx mori silkworm, FDA-approved, used in surgery, tissue engineering, and drug delivery.
• Exhibits in vitro & in vivo biocompatibility, robust mechanical properties (ex. toughness), and relatively slow proteolytic biodegredation.
• Seeding/perfusion & growth of human hepatocarcinoma cell line (HepG2 from ATCC) for 5 days.
Cell concentration: 5 x 108 cells/mL
Cell seeding density: 25,000 cells/cm2
• Silk films: 200 µm thick, cast on PDMS negative molds. 100 mm diameter silicon wafers.
Bettinger, CJ et al. Silk Fibroin Microfluidic Devices. Adv. Mater. 2007 19(5):2847-2850.
Tissue Engineering
• Generally, extrusion-based approaches for fiber production are limited in their ability to precisely control fiber shape, dimension,spatial layouts, and packing densities.
• Bio-MEMS micro-molding processing technology offers the size scale and resolution necessary to mimic native tissue architectures and also the ability to create organized 2-D & 3-D structures as tissue scaffolds.*
• Collagen Type I: strength & mechanical integrity
• Elastin has two functions, resilience and cell seeding in artificial capillaries using polycarbonate & PLGA as a scaffold.
Wang GJ. et al. Bio-MEMS fabricated artificial capillaries for tissue engineering. Microsyst. Technol. (2005) 12:120-127.
SOURCE
http://europepmc.org/articles/pmc3938984
(a) Casting on collagen microfiber network of an elastin-like protein polymer solution. (b) Water soluble tape and PVP dissolution yielding a fiber reinforced elastin composite lamellar sheet. (c) Lamination of multiple fiber reinforced elastin-like protein sheets. (d) Multilamellar sheet fusion and compression at 4°C.
(a) Parylene release layer deposition on a silicon template. (b) Collagen film solvent casting, neutralization, and cross-linking. (c) PVP mask layer solvent casting. (d) Collagen fiber individualization using mechanical polishing and RIE. (e) PVP film casting and water-soluble tape application for fiber network extraction. (f) In-plane collagen fiber network on a water-soluble film.
*Uses silicon wafers & glutaraldehyde.
*Parylene: hydrophobic coating, moisture and dielectric barrier, low friction, used for implanted medical devices, biocompatible/FDA-approved.
Naik, N. et al. Generation of Spatially Aligned Collagen Fiber Networks through Microtransfer Molding. Adv. Healthc. Mater. 2014 March ; 3(3): 367–374. doi:10.1002/adhm.201300112
Microfluidic device:
a) nanometer-scale posts with minimum widths of approximately 400 nm;
b) micrometer-scale fluidic channels;
c,d) Viable cells remained attached and retained function within devices for up to 5 d of perfusion (scale bars are 50 µm).
Bettinger, CJ et al., Silk Fibroin Microfluidic Devices. Adv. Mater. 2007; 19(5):2847-2850.
SOURCE
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677821
Epidermal Electronic Systems (EES)
• EES systems can incorporate electrophysiological, temperature, and strain sensors, as well as transistors, light-emitting diodes, photodetectors, radio frequency inductors, capacitors, oscillators, and rectifying diodes.
• Solar cells and wireless coils provide options for power supply. This EES technology was used to measure electrical activity produced by the heart, brain, and skeletal muscles.
Kim et al. mentioned a correction: Ecoflex®‘modified polyester’ from BASF is replaced with Ecoflex® ‘modified silicone’ from Smooth-On.
Kim, D-H, et al. Epidermal electronics. Science, 333:6044, 12 AUG 2011, p. 838-843.
SOURCE
http://www.ncbi.nlm.nih.gov/pubmed/21836009
A) Schematic of multi-functional electronics for skin Epidermal Electronic System (EES). Mounting is PVA film with electronics facing down. B) EES partially (top) & fully (bottom) peeled away from skin. C) EES on skin undeformed (left), compressed (middle), & stretched (right).
(A) ECG signals measured with an active EES attached to the chest
(left), and magnified view of data corresponding to a single heartbeat (right).
(B) (Left) EMG measurements using an active EES, mounted on the right leg
during simulated walking (from 0 to 10 s) and standing (from 10 to 20 s).
(Right) Recordings collected with conventional sensors and conductive gel.
(C) Spectrogram of the data in (B) for corresponding electrode type.
(D) EMG spectrograms measured using an active EES mounted on the neck during
vocalization of four different words: “up,” “down,” “left,” and “right.”
(E) Simulated video game control by pattern recognition on EMG data from (D).
The player icon is moved from an initial position (red) to destination (green).
(F) (Left) Discrete Fourier transform (DFT) coefficients of EEG alpha rhythms at
~10 Hz (27), measured with a passive EES. (Center) The spectrogram of the
alpha rhythm. The first and next 10 s correspond to periods when the eyes
were closed and open, respectively. The responses at ~10 and ~14 s
correspond to eye opening and blinking, respectively. (Right) Demonstration
of Stroop effects in EEG measured with a passive EES.
SOURCE
http://www.ncbi.nlm.nih.gov/pubmed/21836009
Optical micrograph of a temperature sensor that uses a platinum resistor with serpentine interconnects (left) ; and a strain gauge that uses electrically conductive silicone (CPDMS; right). Serpentine layouts can maintain nearly 20% areal contact of active elements with the skin, for effective electrical interfaces.
SOURCE
http://www.ncbi.nlm.nih.gov/pubmed/21836009
Proteus Digital Health:
• Developed a placebo tablet containing an FDA-approved ingestible event marker (IEM). Conducted clinical trials in UK and is conducting in USA now.
• Raised over $200M. Filed first Digital Medicine NDA with FDA on 9/15.
• Developed DigiMeds – the IEM is now being incorporated into FDA approved drug products in several therapeutic classes (ex. Metformin, Lipitor, Amlodipine, etc.)
• Each IEM has its own unique current signature.
• The patient wears a patch. Once the placebo tablet or DigiMed is ingested it sends an electrochemical signal to the patch and the patch amplifies the signal sent to the patient or the medical provider’s cell phone.
SOURCES
Many patents filed 2014-2015. Some listed below:
• 8,810,409 Multi-mode communication ingestible event markers and
systems, and methods of using the same
• 8,945,005 Controlled activation ingestible identifier
• 9,083,589 Active signal processing personal health signal receivers
• 9,119,554 Pharma-informatics system
• D733,761 Display screen portion having a graphical user interface
for patient monitoring
• 9,107,806 Ingestible device with pharmaceutical product
• 9,149,577 Body-associated receiver and method
• 9,198,608 Communication system incorporated in a container
Patent: # 9,149,423 R. Duck et al., OCT 2015: 20 CLAIMS:
• 1. A device comprising: an ingestible event marker (IEM) comprising: an identifier circuitry component that transmits a conductive signal through a body as a conductive medium when activated, where the conductive signal forms a current signature that identifies the IEM….
and an osmotic ingestible component attached to the IEM, the osmotic ingestible component configured to provide the conductive fluid to the identifier circuitry of the IEM.
• 4. The device of claim 1, wherein the osmotic ingestible component is a tablet.
• 5. The device of claim 1, wherein the osmotic ingestible component is an osmotic capsule comprising: an outer semipermeable layer forming a passageway; and an osmotic member attached to the outer semipermeable layer.
Another mobile healthcare company is iHealth. It has wireless devices to monitor patient health for:
• Blood pressure
• Weight
• Blood glucose
• Body composition analysis $130 (i.e., body fat, water, muscle mass, bone mass, lean mass)
• Oximeter
• Health Edge: Fitness $70 (activity & sleep tracker)
SOURCE
iHealth has a Wireless Patient Monitoring wearable system. The different devices use Bluetooth Smart to send users continuous information including heart, blood pressure, ECG, and health monitoring data straight to their handheld devices.
Conclusions:
• Digital Medicine and its products and technologies are the wave of the future of healthcare.
• According to Yole Development (2014), Bio-MEMS (Medical) sector is expected to grow from $3.0 billion (2015) to $7.3 billion by 2019.
• Technavio’s analysts forecast the global Bio-MEMS and microsystems market in the healthcare sector to grow at a compound annual growth rate (CAGR) of 25.1% over the period 2014-2019. The microfluidic segment constitutes the largest share, growing at a CAGR of almost 27%.
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