Medical device/drug Combination products
As per 21 CFR 3.2(e), combination product is comprised of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product. The combination of similar components, such as a drug-drug or a device-device, is not classified as a combination product per FDA regulations.
Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products.
Types of combination products include:
- Chemically or physically combined products as per 21 CFR 3.2(e)(1): – Eg: drug-eluting stents, patches, implants with drugs, inhalers, drug pumps, insulin pens
- Co-packaged products as per 21 CFR 3.2(e)(2) – Eg: first-aid kits, surgical kits
- Cross-labeled products as per 21 CFR 3.2(e)(3) -Eg: photosensitizing drug with light source
Combination products are classified into device, drug, or biologic based on their primary mode of action (PMOA). For eg, a drug-eluting stent is considered a device because its PMOA is to hold open a clogged artery, whereas a skin patch that slowly releases a hormone is considered a drug because PMOA is the hormone drug effect. Each part of the combination product is evaluated individually in addition to evaluating the entire product as a whole. FDA’s medical product centers, which are made up of the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH) oversee the approval of combination products depending on the classification (“About Combination Products,” n.d.)
In this review development of medical device/drug combination products in the field of implants, diagnostics and drug delivery systems are summarised.The main drivers for the increasing demand for combination products are customer convenience, evolving medicine models and reimbursement strategies, demand for more outpatient and home-health based services (Brown, n.d.).
1. Implantable drug delivery system
Drug delivery is one of the fastest growing areas for implant applications. Drug release and prosthetic performance are coordinated and designed to work in tandem. Implantable devices are broadly divided based on the purpose into three classes: cardiovascular implants, orthopaedic implants and implants for other use (Khan et al., 2014). Implantable drug delivery system offer features:
- Steady state of drug release
- Controlled and tailored delivery of drugs.
- Site specific/targeted drug administration
- Significantly lower dose of drug required
1.1 Cardiovascular implants
Drug-eluting stent (DES) is a peripheral or coronary scaffold placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation. DES prevents scar tissue from growing into the artery and prevent the coronary artery from narrowing again.
1.1a Durable polymer drug-eluting stent
|XIENCE Family||Everolimus||Abbott (“XIENCE Alpine Everolimus Eluting Coronary Stent System,” n.d.)|
|XIENCE PRIME with bioabsorbable polymer|
|XIENCE PRIME LL|
|PROMUS||Everolimus||Boston Scientific (“Coronary Stents – Boston Scientific,” n.d.)|
|TAXUS Express2 Atom|
|Endeavor Sprint||Zotarolimus||Medtronic (“MedtronicStents.com:Resolute Inegrity,” n.d.)|
|Resolute Integrity with BioLinx Polymer|
1.1bBio absorbable polymer drug-eluting stent
Boston Scientific’s SYNERGY coated with Everolimus and Abbot’s Bioresorbable Vascular Scaffold (BVS) known as ABSORB coated with Everolimus are among the gamechangers. They are designed to dissolve into the system within a year to allow the artery to return to normal functioning. Since the stent disappears, it eliminates the cause of potential inflammation that can lead to late-stent thrombosis and restenosis. Most bioresorbable stents are made of polylactic acid. Disadvantages include recoil after expansion,difficulty visualizing a non-metallic stent on fluoroscopy etc (“Bioresorbable Stents Are the Way of the Future,” 2014)
1.2 Orthopaedic implants
Orthopedic implants are primarily designed to support mechanical load in skeleton. Correlating drug delivery with this mechanical support target infection and stimulates the normal bone remodeling process through the release of growth factors. Osteoarthritis and rheumatoid arthritis affect the structure of weight-bearing joints such as the hip and knee. In a total knee arthroplasty, the diseased cartilage surfaces of the lower femur, tibia and the patella are replaced by prosthesis made of metal alloys and polymeric materials. Resorbable calcium phosphate ceramic (CaP) materials,polymers such as methyl-methacrilate as beads or bone cement are used as carrier for antibiotics and growth factors. C alcium phosphate ceramic matrices are suitable carriers for bisphosphonate for bioactive drug delivery system
Drug delivery options used in orthopedic implants are :
- Biomaterials/cement incorporated in scaffold
Biodegradable devices can be used as a foundation for implant based drug delivery, so that the degradation rate allows for the optimal release of the drug or agent to further assist the healing process. Biomet, Johnson & Johnson, Stryker and Zimmer are the leaders in orthopaedic implant industry.
1.3 Other Implants
1.3a Implantable drug pumps
Implantable drug pumps are used to deliver insulin in the treatment of diabetes, administer pain medications directly to the spine (intrathecal pumps). These are typically programmable active devices that require regular resupply of the medication through an access port. Intrathecal pain pump works more efficiently than oral pain medication because it delivers medicine directly into the cerebral spinal fluid, bypassing the path that oral medication takes through the body. The potency of the medication is about 100-300x more with the pump than when taken orally. The pump is programmed to slowly release medication over a period of time. Pain pump may be a treatment option if other traditional methods have failed to relieve long-term symptoms of chronic pain. This has fewer side effects than oral medication.
|Flowonix||Prometra Programmable pump (“Prometra Pump,” 2015)||Infumorph||implanted drug delivery device to deliver the drug to intrathecal space via catheter|
|J&J’s Codman & Shurtleff||MedStream Programmable Infusion Pump (“5. MedStream Programmable Infusion Pump | Qmed,” n.d.)||morphine / Baclofen|
|Medtronic||SynchroMed infusion system (Medtronic, n.d.)||Baclofen|
1.3b Ocular Drug Delivery Implants
Removable or biodegradable ocular inserts can function as controlled-release drug reservoirs. Contact lenses have been used for ocular drug delivery, and their drug-loading capacity can be enhanced by the inclusion of container molecules in their cavities. Ocular implants can provide short-term medication or deliver medication for several years for chronic ocular conditions.
|Retisert||fluocinolone acetonide intraocular implant 0.59 mg||Bausch + Lomb||for chronic noninfectious posterior uveitis (“Retisert (fluocinolone acetonide intravitreal implant) 0.59 mg : Bausch + Lomb,” n.d.)|
|Vitrasert||ganciclovir intravitreal implant 4.5 mg||Bausch + Lomb||cytomegalovirus retinitis (“Vitrasert ImplantSTERILE INTRAVITREAL IMPLANT WITH CYTOVENE®(GANCICLOVIR, 4.5 MG),” n.d.)|
|Ozurdex||dexamethasone intravitreal implant 0.7 mg||Allergan||for macular edema ,central retinal vein occlusion,diabetic macular edema (DME), and posterior uveitis (“OZURDEX® for Diabetic Macular Edema | OZURDEX®,” n.d.)|
|Iluvien||fluocinolone acetonide intravitreal implant 0.19 mg||Alimera Sciences||diabetic macular edema (“ILUVIEN® (fluocinolone acetonide intravitreal implant) 0.19mg for Diabetic Macular Edema (DME) | Alimera Sciences,” n.d.)|
1.3c Contraceptive Devices
Intrauterine devices (IUDs) and intravaginal rings (IVRs), are finding increasing applications in the area of women’s health. Levonorgestrel eluting IUD can aid contraception and treatment for severe menstrual bleeding IVRs are commercially available for contraception, hormone replacement therapy, and to improve the rate ofin vitro fertilization
|Kyleena||Levonorgestrel||Bayer||hormone-releasing IUD (intrauterine device) that prevents pregnancy for up to 3/5 years (“Mirena® IUD Homepage | Official Website,” n.d.)|
|IMPLANON||Etonogestrel||Merck||Matchstick sized flexible implant inserted under the skin of the inner side upper arm (“Implanon NXT – Summary of Product Characteristics (SPC),” n.d.)|
Rather than simply identifying disease, diagnostics are now used to support clinical development of drugs, predict disease before symptoms begin, forecast the progress of a disorder, and identify patients who are most likely to respond to specific treatments.
2.1 Companion diagnostic
As per FDA final guidance “In Vitro Companion Diagnostic Devices” (Aug. 2014 )
companion diagnostic(CoDx) is defined as in vitro diagnostic device that provides information for the safe and effective use of a corresponding therapeutic product
The uses of CoDx are :
- Identify population most likely to benefit or most at risk of adverse reaction a particular therapeutic product
- Monitor response to adjust treatment.
- Identify population for whom product is known to be safe and effective.
These are tailored for use by physicians to help select the right drugs for the right patients. The test helps a health care professional determine whether a particular therapeutic product’s benefits to patients will outweigh any potential serious side effects or risks (Center for Devices and Radiological Health, n.d.).
Companion diagnostics are developed based on companion biomarkers. Biomarkers are biological indicators that are associated with disease. Certain markers of inflammation, blood clotting, and blood vessel function have been associated with risk of cardiovascular disease, stroke and death. Different classes of biomarkers include somatic mutations, polymorphisms, and gene/protein expression profiles linked with a particular disease state
Genomic diagnostic tests make use of genetic biomarkers to combine genetic sequencing and clinical information to help oncologists select the right drugs for their patients, based on mutations in cancer-related genes.CoDx helps in integrating precision medicine in to health care.
2.2a IVD Companion Diagnostic Devices
|Midostaurin||LeukoStrat CDx FLT3 Mutation Assay||Invivoscribe Technologies, Inc.||Somatic gene mutation detection system.IVD test for the selection of patients with acute myelogenous leukemia for whom midostaurin treatment is being considered. Detect specific mutations in the FLT3 gene in genomic DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates of patients diagnosed with AML (“FLT3 Mutation Assay | Invivoscribe,” n.d.)|
|Rubraca||FoundationFocus CDxBRCA Assay||Foundation Medicine, Inc.||detects sequence alterations in BRCA1 and BRCA2 (BRCA1/2) genes.Test results identifyovarian cancer patients for whom treatment with Rubraca™ (rucaparib) is being considered (“FoundationFocusTM CDxBRCA,” n.d.)|
|VENCLEXTA (venetoclax)||Vysis CLL FISH probe kit||ABBOTT Molecular||detects deletion of the LSI TP53 probe target as an aid in identifying those patients with chronic lymphocytic leukemia( CLL) for whom treatment with VENCLEXTA is indicated (“Vysis CLL FISH Probe Kit | Abbott Molecular,” n.d.)|
Table below (Center for Devices and Radiological Health, n.d.)lists some of the FDA approved Breast cancer Companion Diagnostics
|Herceptin||INFORM HER2/NEU||Ventana Medical Systems||FISH|
|PATHWAY ANTI-HER-2/NEU||Ventana Medical Systems||IHC|
|INFORM HER2||Ventana Medical Systems||Dual color ISH|
|PATHVYSION HER-2 Kit||Abbott Molecular||FISH|
|INSITE HER-2/NEU Kit||BioGenex Laboratories||IHC|
|SPOT-LIGHT HER2 Kit||Life Technologies||CISH|
|Bond Oracle HER2 System||Leica Biosystems||IHC|
|HER2 Kit||Dako Denmark||CISH|
Abbreviations : FISH – fluorescence in situ hybridization, ISH – in situ hybridization, IHC – immunohistochemistry, CISH – chromogenic in situ hybridization, HER2- human epidermal growth factor receptor
2.2b Imaging Companion Diagnostic Devices
Diagnostic imaging can be used to monitor and improve treatment responses and patient outcomes (Van Heertum et al., 2015).Resonance Health’s FerriScan R2-MRI Analysis System is an imaging companion diagnostic for deferasirox to detect liver iron concentration.
The system measures liver iron concentration to aid in the identification and monitoring of non-transfusion-dependent thalassemia patients receiving therapy with deferasirox (“FerriScan – MRI Measurement of Liver Iron Concentration – Resonance Health,” n.d.).
2.3 Hand held Companion Diagnostic device
These are designed to overcome the challenges in getting diagnostics to patients in remote locations due to extreme temperatures and lack of trained personnel, cost etc.
|Device||Q-POC point of care device|
|Intended use||Hand-held and portable molecular diagnostic device for precision medicine.As a companion diagnostic and for testing multi-drug-resistant infectious disease including tuberculosis, HIV/AIDS (“QuantuMDx – Molecular Diagnostics in Minutes,” n.d.)|
2.4 Continuous Monitoring Devices – Closed loop sensor and delivery
Smart devices can automate drug delivery in response to realtime patient data. These devices work like the body’s own systems, continually monitoring relevant biomarkers and releasing appropriate doses of moderating drugs or hormones in response. Combining continuous monitoring and insulin delivery allows diabetics and their physicians to control of patients’ blood sugar in response to the body’s needs. Rather than relying on single data points taken at fixed times, the device continuously monitors blood glucose levels to provide dynamic information about glucose levels.
|MiniMed 670G System||Medtronic||Artificial pancreas device system.Continuous monitoring and trending of glucose levels. For continuous delivery of basal insulin (at user selectable rates) and administration of insulin boluses (in user selectable amounts) for the management of Type 1 diabetes mellitus in persons requiring insulin (“MiniMed 670G Insulin Pump System | World’s First Hybrid Closed Loop System,” n.d.)|
|Accu-Check Combo insulin interactive pump||Roche||Combined diagnostics and insulin delivery pumps deliver basal insulin doses and bolus insulin on demand.-high-tech system combining a glucose meter and an insulin pump that communicate via Bluetooth and can be controlled remotely. It even helps patients calculate the best dose. reduce the risk of the long-term complications of diabetes such as kidney disease, sight loss, and heart disease (“Combo system support | Accu-Chek,” n.d.)|
|PaQ insulin delivery device||CeQur||Wearable insulin delivery device that delivers up to 3 days of continuous pre-set basal insulin plus on- demand mealtime bolus.This incorporates a disposable insulin reservoir and a reusable insulin monitor. deliver basal insulin doses and bolus insulin on demand (“CeQur PAQ | CeQur SA. / Corporation,” n.d.)|
3. Drug Delivery Devices
3.1 Transdermal delivery systems
- Dermal Patches provide constant and sustained release profile by properties of capillarity or diffusion/osmosis. Eg: Nicotine and hormone replacement patches
- Electrodynamic patch – works on the principle of iontophoresis
Electromagnetic field created by the patch generates an ion channel that allows efficient absorption of the active ingredients travelling through the skin.
eg: IontoPatch for pain management – Single use and disposable iontophoresis patch with built in battery. Self-contained battery produces an electric current to carry drug molecules non-invasively across the skin and to underlying tissue (“IontoPatch® Electronic Transdermal Iontophoretic Drug Delivery System,” n.d.)
3.2 Microneedle Drug Delivery Systems
The surface of a substrate or material can be coated with very precise tiny pin-like structures which, when applied to the skin can puncture the dead outer layer creating a micro-channel that allows rapid diffusion of the drug. This is painless and depth of penetration carefully controlled. Solid microneedle technology from 3M can deliver vaccines or other biologics up to 300 mcg capacity with efficiency better than injection (“Microneedle Drug Delivery Systems | 3M United States,” n.d.).
3.3 Inhalation Drug Delivery
Different types of Inhalation drug delivery devices are nebulizers, pressurized metered dose inhalers (MDIs), breath-activated inhalers and emerging novel delivery systems. Adding analytics allows patients and healthcare providers to look for patterns in device usage and biometrics over time. Smart inhaler can analyse the patterns of frequency of use to suggest need for more aggressive maintenance therapies. Data is analysed to identify early warning signs and patient response to current medication.
|SmartInhaler||Adherium||Digital solution for respiratory medication.Sensor and data transmission technologies. mobile app with reporting and reminders (“smartinhaler,” n.d.)|
|Propeller||Propeller||Digital platform for respiratory health management. Monitoring device attached to inhalator. Automatically log usage on a mobile app and transmit data to doctors or caregivers (“Propeller Health | Digital Asthma and COPD Management,” n.d.)|
3.4 Scaffold based drug delivery
SurModics, surface modification and drug delivery solutions provider to the medical device industry has exclusive license to two novel classes of biodegradable polymers (PolyActive and OctoDEX) for use in the site specific delivery of drugs from medical devices. PolyActive polymeric drug delivery system is for the controlled release of proteins and lipophilic small molecules for both local and systemic administration. OctoDEX drug delivery system is based on crosslinked dextran microspheres (“Drug Delivery Systems, Drug Delivery Technology: Surmodics Medical Coatings | SurModics: Medical Device Coatings & In Vitro Diagnostics (IVD),” n.d.)
These futuristic devices have the potential to make drug delivery and disease management easier, safer, and convenient for patients and care providers. Overcoming knowledge gaps between the disciplines of technology and medicine is a major problem. Challenges include cybersecurity for connected devices, safety and human factors concerns, and development of the algorithms for drive safe, automated drug delivery. Differences in regulatory pathways for each component of the combination device create an ambiguity in the regulatory processes. There are no universal procedures to follow for harmonized solutions among different countries
5. MedStream Programmable Infusion Pump | Qmed [WWW Document], n.d. URL http://www.qmed.com/mpmn/gallery/image/5-medstream-programmable-infusion-pump (accessed 6.30.17).
About Combination Products [WWW Document], n.d. URL https://www.fda.gov/CombinationProducts/AboutCombinationProducts/ (accessed 6.29.17).
Bioresorbable Stents Are the Way of the Future [WWW Document], 2014. . Diagn. Interv. Cardiol. DAIC. URL https://www.dicardiology.com/article/bioresorbable-stents-are-way-future (accessed 6.29.17).
Brown, W., n.d. 6 Guidelines To Follow When Developing Combination Products [WWW Document]. URL https://www.meddeviceonline.com/docpreview/guidelines-to-follow-when-developing-combination-products-0001/c4ed127d-19b3-4c16-a436-d320cddadb05 (accessed 6.23.17).
Center for Devices and Radiological Health, n.d. In Vitro Diagnostics – Companion Diagnostics [WWW Document]. URL https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407297.htm (accessed 6.23.17a).
Center for Devices and Radiological Health, n.d. In Vitro Diagnostics – List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) [WWW Document]. URL https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm (accessed 6.28.17b).
CeQur PAQ | CeQur SA. / Corporation [WWW Document], n.d. URL http://www.cequrcorp.com/cequr-paq/ (accessed 6.28.17).
Combo system support | Accu-Chek [WWW Document], n.d. URL https://www.accu-chek.com/insulin-pumps-integrated-systems/combo-system/support (accessed 6.29.17).
Coronary Stents – Boston Scientific [WWW Document], n.d. URL http://www.bostonscientific.com/en-US/products/stents–coronary.html (accessed 6.29.17).
Drug Delivery Systems, Drug Delivery Technology: Surmodics Medical Coatings | SurModics: Medical Device Coatings & In Vitro Diagnostics (IVD) [WWW Document], n.d. URL http://www.surmodics.com/medical-device/coating-technologies/drug-delivery-coatings-overview/durable-materials/ (accessed 6.30.17).
FerriScan – MRI Measurement of Liver Iron Concentration – Resonance Health [WWW Document], n.d. URL http://www.resonancehealth.com/products/ferriscan-mri-measurement-of-liver-iron-concentration.html (accessed 6.28.17).
FLT3 Mutation Assay | Invivoscribe [WWW Document], n.d. URL https://www.invivoscribe.com/catalog/flt3-mutation-assay (accessed 6.29.17).
FoundationFocusTM CDxBRCA [WWW Document], n.d. . Found. Med. URL undefined/genomic-testing/foundation-focus (accessed 6.29.17).
ILUVIEN® (fluocinolone acetonide intravitreal implant) 0.19mg for Diabetic Macular Edema (DME) | Alimera Sciences, n.d.
Implanon NXT – Summary of Product Characteristics (SPC) [WWW Document], n.d. URL http://www.medicines.ie/medicine/14810/SPC/Implanon (accessed 6.29.17).
IontoPatch® Electronic Transdermal Iontophoretic Drug Delivery System [WWW Document], n.d. URL http://www.iontopatch.com/device.html (accessed 6.30.17).
Khan, W., Muntimadugu, E., Jaffe, M., Domb, A.J., 2014. Implantable Medical Devices, in: Domb, A.J., Khan, W. (Eds.), Focal Controlled Drug Delivery. Springer US, Boston, MA, pp. 33–59. doi:10.1007/978-1-4614-9434-8_2
Medtronic, n.d. Drug Infusion Systems – SynchroMed II [WWW Document]. URL /us-en/healthcare-professionals/products/neurological/drug-infusion-systems/synchromed-ii.html (accessed 6.30.17).
MedtronicStents.com:Resolute Inegrity [WWW Document], n.d. URL http://www.medtronicstents.com/en/en_integrity_superior_deliverability.html (accessed 6.29.17).
Microneedle Drug Delivery Systems | 3M United States [WWW Document], n.d. URL http://www.3m.com/3M/en_US/drug-delivery-systems-us/technologies/microneedle/ (accessed 6.30.17).
MiniMed 670G Insulin Pump System | World’s First Hybrid Closed Loop System [WWW Document], n.d. URL https://www.medtronicdiabetes.com/products/minimed-670g-insulin-pump-system (accessed 6.29.17).
Mirena® IUD Homepage | Official Website [WWW Document], n.d. . Mirena US. URL https://www.mirena-us.com/ (accessed 6.29.17).
OZURDEX® for Diabetic Macular Edema | OZURDEX® [WWW Document], n.d. URL http://www.ozurdex.com/DME/Ozurdex-for-DME (accessed 6.29.17).
Prometra Pump [WWW Document], 2015. . Flowonix. URL http://www.flowonix.com/healthcare-provider/products/prometra-pump (accessed 6.29.17).
Propeller Health | Digital Asthma and COPD Management [WWW Document], n.d. . Propeller Health. URL https://www.propellerhealth.com/ (accessed 6.30.17).
QuantuMDx – Molecular Diagnostics in Minutes [WWW Document], n.d. URL http://quantumdx.com/ (accessed 6.28.17).
Retisert (fluocinolone acetonide intravitreal implant) 0.59 mg : Bausch + Lomb [WWW Document], n.d. URL http://www.bausch.com/ecp/our-products/rx-pharmaceuticals/rx-pharmaceuticals/retisert-fluocinolone-acetonide-intravitreal-implant-059-mg (accessed 6.29.17).
smartinhaler [WWW Document], n.d. URL http://www.smartinhaler.com/ (accessed 6.30.17).
Van Heertum, R.L., Scarimbolo, R., Ford, R., Berdougo, E., O’Neal, M., 2015. Companion diagnostics and molecular imaging-enhanced approaches for oncology clinical trials. Drug Des. Devel. Ther. 9, 5215–5223. doi:10.2147/DDDT.S87561
Vitrasert ImplantSTERILE INTRAVITREAL IMPLANT WITH CYTOVENE®(GANCICLOVIR, 4.5 MG) [WWW Document], n.d. URL https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=18322 (accessed 6.29.17).
Vysis CLL FISH Probe Kit | Abbott Molecular [WWW Document], n.d. URL https://www.molecular.abbott/int/en/products/oncology/vysis-cll-fish-probe-kit (accessed 6.29.17).
XIENCE Alpine Everolimus Eluting Coronary Stent System [WWW Document], n.d. URL http://www.vascular.abbott/us/products/coronary-intervention/xience-alpine-drug-eluting-stent.html (accessed 6.29.17).
Cite This Work
To export a reference to this article please select a referencing stye below:
Related ServicesView all
Related ContentAll Tags
Content relating to: "Medical Technology"
Medical Technology is used to enhance the medical care and treatment that patients are given in healthcare settings. Medical Technology can be used to identify, diagnose and treat medical conditions and illnesses.
Role of Imaging in Early Diagnosis of Acute Ischemic Stroke
This literature review aims to provide a clinical review of the advantages and disadvantages of different available neuroimaging methods in approaching acute stroke to help clinicians choose the best method according to the settings....
Septal Occlusion Devices for the Closure of Ostium Secundum type Atrial Septal Defects
A Meta Analysis of Septal Occlusion Devices compared against Cardiac Surgery for the closure of Ostium Secundum type Atrial Septal Defects: Safety, Efficacy and Costs....
3D Printing for Medical Simulation of Airway Emergencies in Paediatric Anaesthesia
Technological advances in 3D printing have resulted in increased use of this technology in the medical practice, coupled with its increasing availability and decreasing cost makes it a desirable technology to investigate for production of an infant airway trainer....
DMCA / Removal Request
If you are the original writer of this dissertation and no longer wish to have your work published on the UKDiss.com website then please: