6.2.1.2.Use of Iridium in Medical Applications
Iridium and its alloys with platinum have been and continue to be used as control materials or as portions of new devices in biomedical engineering research. Applications include a variety of medical implants that take advantage of either the strength or the electrical properties of these metals for dental, osteological, neurological (both peripheral and central nervous system), and cardiovascular applications. The following references describe the use of iridium in several medical applications:
1. Agnew, W.F., Yuen, T.G., McCreery, D.B., & Bullara, L.A. (1986). Histopathologic evaluation of prolonged intracortical electrical stimulation. Experimental Neurology, 92, 162-185.
2. Niparko, J.K., Altschuler, R.A., Wiler, J.A., Xue, X., and Anderson, D.J. (1989) Surgical implantation and biocompatibility of central nervous system auditory processes. Annals of Otology, Rhinology and Laryngology, 98, 965-970.
3. Walter, J.S., McLane, J., Cai, W., Khan, T., & Cogan, S. (1994). Evaluation of a thin-film peripheral nerve cuff electrode. The Journal of Spinal Cord Medicine, 18, 28-32.
4. McCreery, D.B., Agnew, W.F., & McHardy, J. (1987). Electrical characteristics of chronically implanted platinum-iridium electrodes. IEEE Transactions on Biomedical Engineering, 34, 664-668.
5. Hochmair-Desoyer, I., & Hochmair, E.S. (1980). An eight channel scala tympani electrode for auditory prostheses. IEEE Transactions on Biomedical Engineering , 27, 44-50.
6. Ison, K.T., & Walliker, J.R. (1987). Platinum and platinum/iridium electrode properties when used for extracochlear stimulation of the totally deaf. Medical & Biological Engineering & Computing, 25,403-413.
7. Del Bufalo, A.G., Schlaepfer, J., Fromer, M., & Kappenberger, L. (1993). Acute and long-term ventricular stimulation thresholds with a new, iridium oxide-coated electrode. Pacing& Clinical Electrophysiology, 16, 1240-1244.
8. Bolz, A., Hubmann, M., Hardt, R., Riedmuller, J., & Schaldach, M. (1993). Low polarization pacing lead for detecting the ventricular-evoked response. Medical Progress through Technology, 19, 129-137.
6.3.Borosilicate glass
The BION™ capsule is made up of Kimble N51A borosilicate glass. This material is used for drug vials and laboratory glassware because of its long term stability and low solubility and lack of reaction with a wide range of biochemical entities.
2.2. Biocompatibility as judged by in vitro and in vivo testing
Biocompatibility of the device was determined by a literature review of research performed on each component material of the device (discussed above) and by studies performed by various researchers and qualified personnel at NAmSA Laboratories, Irvine, California. All biological (biocompatibility) evaluations, including microbiological and toxicological evaluations, were conducted in compliance with Good Laboratory Practices (U.S. Title 21 CFR Part 58).
2.2.1. Published Pre-Clinical Research
Several articles have been published in peer-reviewed journals regarding the design and fabrication of BIONs™ as well as the biocompatibility of BIONs™ in animals (Appendix 2). These include:
Peer-reviewed articles
1. Loeb, G.E., Zamin, C.J., Schulman, J.H., Troyk, P.R. (1991) Injectable microstimulator for functional electrical stimulation. Medical and Biological Engineering and Computing 29:NS13-NS19.
2. Cameron, T., Loeb, G.E., Richmond, F.J.R., Peck, R.A., Schulman, J.H., Strojnik, P., Troyk, P. (1993). Micromodular electronic devices to activate paralyzed muscles and limbs. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 15: 1242-1243.
3. Cameron, T., Misener, D.L., Peck, R.A., Dupont, A.C., Olney, S., and Loeb, G.E. (1995) A bedside controller for use with Micromodular Electronic Devices. Annual International Conference IEEE-EMBS, 17: 1163-4 (#5.4.6.14).
4. Loeb, G.E., Peck, R.A., and Martyneiuk, J. (1995) Toward the ultimate metal
microelectrode. Journal of Neuroscience Methods 63:175-183.
5. Loeb, G.E., Peck, R.A., and Smith D.W. (1995) Microminature molding techniques for cochlear electrode arrays. Journal of Neuroscience Methods 63:85-92.
6. Fitzpatrick, T.L., Liinamaa, T.L., Brown, I.E., Cameron, T. and Richmond, F.J.R. (1996). A novel method to identify migration of small implantable devices. Journal of Long-Term Effects of Medical Implants. 6, 157-168.
7. Loeb G.E. and Peck, R.A. (1996) Cuff electrodes for chronic stimulation and recording of peripheral nerve activity. Journal of Neuroscience Methods 64:95-103.
8. Cameron, T., Loeb, G.E., Peck, R.A., Schulman, J.H., Strojnik, P., and Troyk, P.R. (1997). Micromodular implants to provide electrical stimulation of paralyzed muscles and limbs. IEEE Transactions on BME, 44, 781-790.
9. Loeb, G.E., Richmond, F.J.R., Olney, S., Cameron, T., Dupont, A.C., Hood, K., Peck, R.A., Troyk, P.R., Schulman, J.H. (1998). Bionic neurons for functional and therapeutic electrical stimulation. 20th Annual IEEE-EMBS, Hong Kong.
10. Cameron, T., Liinamaa, T.L., Loeb, G.E., Richmond, F.J.R. (1998a). Long-term biocompatibility of a miniature stimulator implanted in feline hind limb muscles. IEEE Transactions on BME, 45, 1024-1035.
11. Cameron, T., Richmond, F.J.R., and Loeb, G.E. (1998b). Effects of regional stimulation using a miniature stimulator implanted in feline posterior biceps femoris. IEEE Transactions on BME 45, 1036-1043.
12. Loeb, G.E. and Richmond, F.J.R. (2000) BION™ implants for Therapeutic and Functional Electrical Stimulation. In: Neural Prostheses for Restoration of Sensor and Motor Function. Crain, J.K., Moxon, K.A., and Gaal, G., eds. CRC Press: Boca Raton.
13. Richmond, F.J.R., Bagg, S.D., Olney, S.J., Dupont, A.C., Creasy, J., and Loeb G.E. (2000) Clinical trial of BIONs™ for therapeutic electrical stimulation. Proceedings of the 5th Annual Conference of the International Functional Electrical Stimulation Society: Aarlburg, Denmark.
14. Dupont, A.C., Loeb, G.E., and F.J.R. Richmond (2000) Effects of chronic stimulation patterns in an animal model of disuse atrophy. Proceedings of the 5th Annual Conference of the International Functional Electrical Stimulation Society: Aarlburg, Denmark.
Abstracts, reviews, and unreviewed proceedings
1. Loeb, G.E. (1983) The biocompatibility of electrically active implants. In: Mechanisms of Hearing. Proceedings of I.U.P.S. Satellite Symposium, Monash University, Australia.
2. Loeb, G.E. (1987) Restoring motor function through electrical stimulation. MS Quarterly Report 6:47-50.
3. Cameron, T., Misener, D.L., Peck, R.A., Dupont, A.C., Olney, S., Loeb, G.E. (1995). A therapeutic electrical stimulation (TES) system for the rehabilitation of muscles after surgery or injury. Annual Meeting Networks of Centres of Excellence for Neural Regeneration and Recovery, Montreal, Quebec 106.
4. Dupont, A.C., Hood, K., Cameron, T., Olney, S., and Loeb, G.E. (1997) Clinical system for the management of therapeutic electrical stimulation. CMBEC, (Toronto).
5. Cameron, T., Liinamaa, T.L., Richmond, F.J.R., and Loeb, G.E. (1997). Muscle
recruitment characteristics of an injectable miniature stimulator. CMBEC (Toronto).
6. Dupont, A.C., Richmond, F.J.R., and Loeb, G.E. (2001) Electrical stimulation via
BIONs™: Present and future applications. Proceedings of Technology and Persons with Disabilities Conference. http://www.csun.edu/cod/conf2001/proceedings/0037dupont.html
7. Romano, C.L., Romano, D. Caserta, S., Loeb, G.E., and Richmond, F.J.R. (2001) BION™ injectable neuromuscular stimulator: clinical trials. SICOT (Internationale de Chirurgie Orthopedique et de Traumatologie) (Paris).
In early studies, the nature of the foreign-body response evoked by microstimulators was compared to that obtained in the same animals following implant of glass bullets of similar size for a period of 1-3 months (Fitzpatrick et al., 1996). The capsules around the microstimulators were found to be equivalent in thickness to those around the glass capsules, and were slightly thinner than those around the 6-0 EthibondTM (polyethylene terephthalate coated with polybutilate) sutures marking the site of implant on the muscle surface. In the same studies it was possible to analyze the propensity of the implanted devices to migration. A novel method was developed in which a fluorescent dye was applied onto the device using molten glucose; the dissolution of the dye immediately after implant marked the spot in which the device was first lodged. By using glass bullets with ends of differing tapers as well as microstimulators, Fitzpatrick et al. (1996) showed that migration was an unlikely consequence even when devices had pointed ends. Only one device with a sharp end migrated more than a few millimeters. That device had been implanted inappropriately with its leading, sharp tip pushed beyond the deep surface of the target muscle. All other devices were held securely within a thin fibrous capsule at the site of initial implantation. The microstimulators seemed especially well anchored because connective tissue grew around the necks of the electrodes at either end. See Figure 1. In this and later studies, it was found to be necessary to cut this adherent connective tissue when the devices were removed from muscles at necropsy.
Figure 1: Microstimulator Extraction
Figure 1. Gross appearance of tissues around tantalum electrode of microstimulator. Note the absence of a visible connective tissue layer (A), yet strands of collagenous material are seen clinging to the electrode when the device is extruded (B).
Foreign-body responses and associated muscular changes were examined more specifically by implanting active microstimulators, passive microstimulators and device components into the hindlimb muscles of 5 cats for up to three months (Cameron, 1998b). Active and passive microstimulators evoked essentially identical foreign-body reactions and were enveloped by capsules of equivalent thickness. The thickness of the surrounding loose inflammatory cells and fibrous capsule was 0.25mm. This value was similar to that evoked around braided 6-0 polyester sutures coated with polybutylate (Figure 2), and much more modest than the reactions around small pieces of broken glass. They were, however, slightly larger than reactions around soft silicone tubing. The modest thickness of the encapsulating connective tissues did not interfere with the capacity of the device to stimulate tissue, because thresholds measured at weekly intervals during the post-implantation survival period did not change significantly over time. An unexpected finding was the difference in capsule thickness seen around devices implanted in different target muscles. Medial gastrocnemius, a highly active muscle during normal cat locomotion, exhibited a slightly larger foreign-body response than tibialis anterior, a flexor with a more intermittent pattern of activity. This result suggested that the level of activity of the muscle affected the degree of reaction to the implanted device. The placement of devices into the highly active limb muscles of normal, uncaged cats was felt to constitute a more stringent test of compatibility than implantations into paraspinal muscles of sedentary or restrained rabbits, a common screening test for biomaterials.
Figure 2: Cumulative Frequency Graph of Capsule Thickness
Fig 2. This graph depicts the cumulative frequency of capsules with increasing thickness around passive and active devices, as well as around suture material. This graph illustrates that the capsules around the passive and active devices were very similar, but capsule thickness around sutures were slightly greater.
Chronic biocompatibility studies have been paralleled by acute animal trials in which the extent of muscle territories activated by implanted devices were studied in anaesthetized cats (Cameron et al., 1998; Singh et al., 2000). Results suggested that the force output of a muscle could be graded effectively by grading the current strength and the pulse width of the electrical stimulus. Glycogen-depletion methods further showed that the territory activated by the device was affected by the site of placement. Devices implanted near an entering muscle nerve were more effective at recruiting large subvolumes of muscle fibers than devices implanted at a distance from the same nerve bundle. However, devices implanted at some distance from the main nerve were more useful for grading force output in smaller steps. This is similar to results obtained by Grandjean and Mortimer (1986) with surgically implanted epimysial electrodes.
Devices that were implanted for up to three months in muscle were evaluated using dissecting microscopy and scanning environmental electron microscopy for evidence of damage or deterioration (Cameron et al., 1997). The analyses found no changes in the surface of the microstimulators. Of the 12 implanted devices all but one functioned normally at the end of the experiment. The device that stopped functioning was found to contain water vapor which had entered through small cracks in the glass seal at the Ta end. This crack was thought to have developed over time because of residual stress in the glass after sealing. This problem has since been subjected to intensive engineering study and manufacturing modifications. In addition, a high pressure bomb test has been implemented to identify devices with such flaws.