1.1.
Background of the BION™Project
The basic form, function, and technology for the BION™ was identified by Dr. Gerald E.
Loeb about the time that he joined the Bio-Medical Engineering Unit at Queen's
University, Kingston, Ontario, Canada, in 1988.
The principles underlying its
manufacture stem from injectable transponder technology, now in widespread use for
identifying pets and livestock, on which Dr. Loeb worked as a consultant in the 1980s.
Disclosure of the concept for an injectable microstimulator to the Neural Prosthesis
Program of the National Institutes of Health (National Institute of Neurological Disorders
and Stroke) led to the first of a series of research contracts to the A.E. Mann Foundation
for Scientific Research in Sylmar, California. The contracts provided funds to a
triumvirate of research teams at the Mann Foundation (Joseph Schulman, Principal
Investigator), Queen's University in Kingston, Ontario (Gerald Loeb and Frances
Richmond, Principal Investigators), and the Illinois Institute of Technology in Chicago,
Illinois (Philip Troyk, Principal Investigator), who have been developing and testing
working models of the implantable microstimulator. More recently, these contracts have
also included the development of bidirectional telemetry links that will eventually be used
for complete functional neuromuscular control systems based on sensory feedback and
command signals recorded from within the body. For the past five years, work at
Queen's University has concentrated on fabrication of prototype microstimulators and
preparation for clinical trials, including long term testing in animals and development of
electronic hardware and computer software to permit therapists to create stimulation
programs that therapists can administer in the clinic and study participants can
administer later at home.
This research has been funded by the Canadian
Neuroscience Network of Centres of Excellence and by the Ontario Rehabilitation
Technology Consortium.
Clinical trials that involve small groups of subjects are currently underway in Canada and
in Italy (see discussion below). The study in Canada is intended to evaluate the safety
and efficacy of intramuscular stimulation with BIONs™ to improve the strength, range of
motion and, health of muscles and joints in the upper extremities of subacute stroke
survivors. The aim of the study in Italy is to evaluate the safety and efficacy of
neuromuscular stimulation delivered by BIONs™ for the treatment of quadriceps
muscular hypotrophy in individuals with osteoarthritis. In the combined trials, a total of
nine study participants have received BION™ treatment with no adverse effects.
1.2.
Design Philosophy
The overall objective of this project is to provide a practical way to stimulate and
exercise paralyzed muscles. In order to be practical, the technology must combine
precise and reliable stimulation with ease and flexibility of use while minimizing costs
and risks associated with implantation. The following three key factors dictated the
unique design of the BION™ implants:
1.
Size – One of the primary determinants of biocompatibility is the size of the
implanted object. Both surface area and mass can affect the body’s response to
nominally “biocompatible” materials. It was a primary design goal of this project to
produce a modular implant that was as small as possible and which could operate
without being linked physically by connectors and leads to a source of power or control.
2. Implantation – The method of implantation itself entails substantial risk of
complications and morbidity, particularly if it entails invasive surgery in debilitated
individuals. It was a primary design goal of this project to produce an implant with a form
factor that permitted it to be implanted and reliably located by percutaneous injection
rather than surgery.
3. Operation without leads – Perhaps the largest source of reliability problems in any
electronic device arise from connectors and cables within and between devices. This is
particularly so for implanted electronic devices which must survive constant motion while
immersed in the saline fluids of the body. It was a primary design goal of this project to
produce an implant that received data and power entirely by wireless means and that
delivered its stimulation pulses via electrodes affixed rigidly to a rigid package.
2.
PRIOR INVESTIGATIONS
Four aspects of investigation are important in evaluating the safety and efficacy of a
medical device:
1. suitability of materials suggested by previous research and publications
2. biocompatibility as judged by in vitro and in vivo testing
3. safety and efficacy in animals
4. safety and efficacy in humans
2.1.
Suitability of Materials
The BION™ implant is composed of electronic components contained in a borosilicate
glass capsule sealed hermetically to tantalum and iridium electrodes at either end of the
device.
2.1.1. Prior Research
The tantalum and iridium electrodes and the borosilicate glass capsule are the materials
that are in direct contact with bodily fluids. The biocompatibility of these materials has
been well documented in previous biocompatibility studies that have been reported in
the literature.
2.1.1.1.
2.1.1.1.1.
TANTALUM (Ta)
Physicochemical Properties
Tantalum is a metal that is almost completely immune to chemical attack at
temperatures below 150°C. It is degraded only by hydrofluoric acid, acidic solutions
containing fluoride ions, and free sulfur trioxide.1 Tantalum tested in Ringer’s solution
and in a low pH solution (to mimic the environment of inflamed tissue), showed no
significant reduction in its fatigue properties.2 Further, tantalum is very resistant to
corrosion. A semi- or non-conductive oxide layer forms spontaneously on the surface of
tantalum which prevents any exchange of electrons and thus any redox reaction at the
surface.3,4,5 This ability to resist corrosion makes tantalum highly regarded for
applications such as neuromuscular stimulation, in which pulses of current are delivered
repetitively.
1.
2.
3.
4.
5.
CRC Handbook of Chemistry and Physics (1981). R.C. Weast, ed. CRC Press, Inc.
Boca Raton, Florida.
Weiss, B., Stickler, R., Schider, S., Schmidt, H. (1982) Corrosion fatigue testing of
implant materials (Nb, Ta, stainless steel) at ultrasonic frequencies. In: Ultrasonic
Fatigue: Proceedings of the First International Conference on Fatigue and Corrosion
Fatigue up to Ultrasonic Frequencies. (pp. 387-411). Warrendale, PA: Metallurgical
Society of AIME.
Evans, U.R. (1963). An Introduction to Metallic Corrosion. London: Edward Arnold
Ltd.
Glantz, P., Bjorlin, G., & Sundstrom, B. (1975). Tissue reactions to some dental
implant materials. Odont Review, 26, 231-238.
Sharma, C.P., & Paul, W. (1992). Protein interaction with tantalum: changes with
oxide layer and hydroxyapatite at the interface. Journal of Biomedical Materials
Research, 26, 1179-1184.
2.1.1.1.2.
Electrochemical Characteristics
The following references examine the electrochemical characteristics of tantalum
electrodes and assess the use of tantalum in chronic stimulation. They show that the
particular form of anodized, sintered tantalum used in the BION™ implants is a safe and
effective electrode for long-term stimulation of tissue and that it effectively prevents the
passage of direct current which can cause tissue damage of the kind that can be
provoked with other types of electrodes.
1.
2.
3.
4.
5.
6.
Bernstein, J.J., Hench, L.L., Johnson, P.F., Dawson, W.W., & Hunter, G. (1977).
Electrical stimulation of the cortex with tantalum pentoxide capacitive electrodes. In
F.T. Hambrecht & I.B. Reswick (Eds.), Functional Electrical Stimulation: Applications
in Neural Prostheses. (pp. 465-477). New York: Marcel Dekker .
Guyton, D.L., & Hambrecht, F.T. (1973). Capacitor electrode stimulates nerve or
muscle without oxidation-reduction. Science, 181, 74-76.
Guyton, D.L., & Hambrecht, F.T. (1996). Theory and design of capacitor electrodes
for chronic stimulation. Medical and Biological Engineering, 12, 613-619.
Johnson, P.F., Bernstein, J.I., Hunter, D.W., Dawson, W.W., & Hench, L.L. (1977).
An in vitro and in vivo analysis of anodized tantalum capacitive electrodes:
Corrosion response, physiology, and histology. Journal of Biomaterials
Research,11, 637-656.
Rose, T.L., Kelliher, E.M., & Robblee, L.S. (1985). Assessment of capacitor
electrodes for intracortical neural stimulation. Journal of Neuroscience Methods, 12,
181-193.
Schmidt, E.M., Hambrecht, F .T., & McIntosh, I.S. (1982). Intracortical capacitor
electrodes: Preliminary evaluation. Journal of Neuroscience Methods, 5, 33-39.
2.1.1.1.3.
Biocompatibility
A broad range of experiments has been performed to test the biocompatibility of
tantalum in various tissue types. Different forms of tantalum have been implanted into
numerous target tissues with little or no adverse tissue reaction. The following animal
studies examined the effects of tantalum on various tissue types:
1.
Fontaine, A.B., Dake, M.D., Tschang, T., Stabbe, M.T., & Dos Passos, S. (1993).
Tantalum balloon-expandable stent: in vivo swine studies. Journal of Vascular
Interventional Radiology, 4, 749-752.
2. Scott, N.A., Robinson, K.A., Nunes, G.L., Thomas, C.N., Viel, K., King, S.B., Harker,
L.A., Rowland, S.M., Luman, I., & Cipolla, G.D. (1995). Comparison of the
thrombogenicity of stainless steel and tantalum coronary stents. American Heart
Journal, 129(5), 866-72.
3. Samuels, P.B., Roedling, H., Katz, R., & Cincotti, J.I. (1966). A new hemostatic clip:
2-year review of 1007 cases. Annals of Surgery, 163, 427.
4. Robinson, I.D., Yedlicka, I. W., Bildsoe, M.C., Vlodaver, Z., Hunter, D. W.,
Castaneda-Zuniga, W ., & Amplatz, K. (1990). The biocompatibility of compressed
collagen foam plugs. Cardiovascular and Interventional Radiology, 13, 36-39.
5. Nadel, J.A., Wolfe, W.G., & Graf, P.D. (1968). Powdered tantalum as a medium for
bronchography in canine and human lungs. Investigative Radiology, 3, 229.
6. Aronson, A.S., Ionsson, N., & Alberius, P. (1985). Tantalum markers in
radiography. Skeletal Radiology, 14, 207 -211.
7. Alberius, P. (1998). Bone reactions to tantalum markers. A scanning electronic
microscope study. Acta Anatomica (Basel), 115, 310.
8. Michel, R., Reich, M., Notle, M., Rabenseifner, L., Horn, E.M., & Holm, R. (1988).
INAA of rabbit tissues and organs after application of tantalum implants. Trace
Element Analytical Chemistry in Medicine and Biology, 504-512.
9. von HoIst, H., Collins, P ., & Steiner, L. (1981 ). Titanium, Silver, and Tantalum Clips
in brain tissue. Acta Neurochirurgica, 56,239-242.
10. Cardella, J.F., Wilson, R.P., Fox, P.S., & Griffith, J.W. (1995). Evaluation of a
second-generation tantalum biliary stent in a canine model. Journal of Vascular &
Interventional Radiology, 6, 397-403.
11. Bosnjakovic, P., Ilic, M., Ivkovic, T., Kutlesic, C., Mihailovic, D., Savic, V., &
Petkovic, B. (1994). Flexible tantalum stents: effects in the stenotic urethra.
Cardiovascular and Interventional Radiology, 17, 280-284.
2.1.1.1.4.
The Use of Tantalum in Medical Applications
Because of its desirable physiochemical properties and biocompatibility, tantalum has
been used successfully as a material for implants in medicine for over thirty years.
Tantalum has been used as a material for joint prostheses, bone replacements and
repair, suture wire, cranial repair plates, and radiographic markers.
1.
2.
3.
Issa, T.K., Bahgat, M.A., & Linthicum, F.H., Jr. (1983). Tissue reaction to prosthetic
materials in human temporal bones. The American Journal of Otology,5, 40-43.
Grundshober, F., Kellner, G., Eschberger, J., & Plenck, H.J. (1980). Long-term
osseus anchorage of endosseus dental implants made of tantalum and iridium. 1st
World Biomaterials Congress, Baden, 365(abstract).
Kobayashi, H., Hayashi, M., Kawano, H., Handa, Y., Kabuto, M., & Tsuji, T. (1986).
Treatment of blow-out fracture. Neurological Research, 8,221-224.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
McFadden, J.T. (1989). Evolution of the crossed-action intracranial aneurysm clip.
Technical note. Journal of Neurosurgery, 71, 293-296.
Strecker, E.P., Boos, I.B., & Hagen, B. (1996). Flexible tantalum stents for the
treatment of iliac artery lesions: long-term patency, complications, and risk factors.
Radiology, 199,641-647.
Strecker, E.P., Hagen, B., Liermann, D., Schneider, B., Wolf, H.R., & Wambsganss,
J. (1993). Iliac and femoropopliteal vascular occlusive disease treated with flexible
tantalum stents. Cardiovascular and Interventional Radiology,16(3), 158-164. 
Ozaki, Y., Keane, D., Nobuyoshi, M., Hamasaki, N., Popma, J.J., & Serruys, P.W.
(1995). Coronary lumen at six-month follow-up of a new radiopaque Cordis tantalum
stent using quantitative angiography and intracoronary ultrasound. American
Journal of Cardiology, 76, 1135-1143.
Gamsu, G., & Nadel, J.A. (1972). New technique for roentgenographic study of
airways and lungs using powdered tantalum. Cancer,30, 1353-1357.
Zamel, N., Austin, J.H., Graf, P.D., Dedo, H.H., Jones, M.D., & Nadel, J.A. (1970).
Powdered tantalum as a medium for human laryngography. Radiology, 94, 547-553.
Lawson, T.L., Margulis, A.R., Nadel, J.A., Rambo, O.N., & Wolfe, W.G. (1969).
Intraperitoneal introduction of tantalum powder. A roentgenographic and
pathologic study. Investigative Radiology, 4, 293-300.
Gerstenberg, T .C., Praetorius, B., Nielsen, M.L., Clausen, S., & Lindenberg, S.
(1983). Sterilization by vas occlusion without transection does not reduce
postvasectomy sperm-agglutinating bodies in serum. A randomized trial of vas
occlusion versus vasectomy. Scandinavian Journal of Urology & Nephrology, 17,
149-151.
Bjork, A. (1968). The use of metallic implants in the study of facial growth in
children: method and application. American Journal of Physical Anthropology, 29,
243-254.
Bjork, A., Sarnas, K.V., & Rune, B. (1995). Intramatrix rotation--the frontal bone.
European Journal of Orthodontics, 17, 3- 7.
Trope, C., & Selvik, G. (1997). Antineoplastic drug effect evaluated with a new X-ray
stereographic measurement of the tumor volume. Current Chemotherapy, 1137.
Sarnat, B.G., & Selman, A.l. (1978). Growth pattern of the rabbit nasal bone region.
a combined serial gross and radiographic study with metallic implants. Acta
Anatomica (Basel), 101, 193.
Rubenstein, L.K., Strauss, R.A., Lindauer, S.l., Davidovitch, M., & Isaacson, R.l.
(1993). Tantalum implants as markers for evaluating postoperative orthognathic
surgical changes. International Journal of Adult Orthodontics & Orthognathic
Surgery,8(3), 203-209.
2.1.1.1.5.
Surface Characteristics and Biocompatibility of Tantalum
In the present device, Ta powder is packed onto the end of the Ta stem forming a slug,
in a process called sintering. This increases the surface area for charge storage and
allows the discharge of currents larger than would be possible using a solid tantalum
pellet. One might question whether a sintered slug would produce a more intense
reaction because of its rough surface. However, the surface roughness of various forms
of Ta has been shown not to make a difference, probably because the pore sizes are
very small and the grains are individually smooth rather than sharp at cellular
dimensions. Meenaghan et al.1 compared the tissue reactions to various forms of Ta
implanted into the subcutaneous paravertebral region of the monkey. Ta slugs were
prepared in various ways: mill finished, metallurgically polished, electrochemically
oxidized, and sintered with porous surface. Within the groups of devices manufactured
using different methods, one subgroup was glow-discharged and one was not. The study
showed that regardless of surface roughness, the tissue response was remarkably
similar. However, tissues around implants that were glow-discharged showed a
significantly greater cellular response. Meenaghan et al.1 postulated the surface energy
of the implant is perhaps more important than the surface texture. Other studies have
supported this study, showing that porous Ta has no greater effect than non-porous
materials on tissue reaction and that in some cases its performance is better.
1.
2.
Meenaghan, M.A., Natiella, l.R., Moresi, l.L., Flynn, H.E., Wirth, l.E., & Baier, R.E.
(1979). Tissue response to surface treated tantalum implants: preliminary
observations in primates. Journal of Biomedical Materials Research, 13, 631-643.
Guarda, F., Galloni, M., Assone, F., Pasteris, V., & Luboz, M.P. (1982). Histological
reactions of porous tip endocardial electrodes implanted in sheep. International
Journal of Artificial Organs, 5(4), 267-273.
2.1.1.2.
IRIDIUM (Ir)
2.1.1.2.1.1. Physical/Chemical properties
Iridium and its alloys with platinum are materials with mechanical properties similar to
stainless steel. Iridium has excellent electrical conduction properties in the bulk metal
and its interface with saline body fluids. The electrical characteristics of iridium
electrodes have been well-documented.1,2 Excellent long-term biological performance is
also characteristic of iridium and other noble metals because the release of metal ions to
tissues is minimal. Iridium is described in the CRC Handbook of Chemistry and Physics
as the most corrosion-resistant element known. Iridium has been used to coat various
materials to decrease problems associated with corrosion of the underlying materiaI3,4.
1.
2.
3.
4.
Beebe, X., & Rose, T.L. (1988). Charge injection limits of activated iridium oxide
electrodes with 0.2 ms pulses in bicarbonate buffered saline. IEEE Transactions on
Biomedical Engineering, 35, 494-495.
Robblee, L.S., Mangaudis, M.J., Jasinsky, E.D., Kimball, A.G., & Brummer, S.B.
(1986). Charge injection properties of thermally prepared iridium oxide films.
Material Research Society Symposium Proceedings, 55, 303-310.
Buchanan, R.A., Lee, I.S., and Williams, J.M. (1990). Surface modification of
biomaterials through noble metal ion implantation. Journal of Biomedical Materials
Research, 24,309-318.
Lee, I.S., Buchanan, R.A., and Williams, J.M. (1991). Charge-injection densities to
iridium and iridium ion implanted TI-6AI-4V with relevancy to neural stimulation.
Journal of Biomedical Materials Research, 25, 1039-1041.
2.1.1.2.1.2. 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.
2.
3.
4.
5.
6.
7.
8.
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.
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.
Walter, J.S., McLane, J., Cai, W., Khan, T., & Cogan, S. (1994). Evaluation of a thinfilm peripheral nerve cuff electrode. The Journal of Spinal Cord Medicine, 18, 28-32.
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.
Hochmair-Desoyer, I., & Hochmair, E.S. (1980). An eight channel scala tympani
electrode for auditory prostheses. IEEE Transactions on Biomedical Engineering ,
27, 44-50.
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.
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.
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.
2.1.1.3.
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.
2.
3.
4.
5.
6.
7.
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.
Loeb, G.E. (1987) Restoring motor function through electrical stimulation. MS
Quarterly Report 6:47-50.
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.
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).
Cameron, T., Liinamaa, T.L., Richmond, F.J.R., and Loeb, G.E. (1997). Muscle
recruitment characteristics of an injectable miniature stimulator. CMBEC (Toronto).
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
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
10 0
90
80
70
Cu m u l a t i v e
Fr e q u e n c y
(%)
60
50
Pa s s i v e
40
Ac t iv e
30
Su t u r e
20
10
0
0. 0
0. 2
0. 4
0. 6
1. 0
Ca p s u l e Th i c k n e s s ( m m )
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.
2.2.2. Unpublished Pre-clinical Studies
NAmSA Laboratories, 9 Morgan St., Irvine, California 92618, worked with us to perform
biocompatibility studies pursuant to the FDA Tripartite and ISO 10993 guidelines which
recommend a certain combination of tests for a device that will be permanently
implanted in the body. Three types of tests were carried out: in vitro, short-term in vivo,
and long-term in vivo tests. Because devices are so small (~0.14g), a particularly large
number of devices are required for these tests. Since it would be exceptionally
expensive to develop a large stock of functionally active devices, the assembly
procedure for the BIONs™ was modified. Instead of attaching electrodes at either end
of the glass capsule, the capsules were sealed using the same laser-welding techniques
that are used for functioning devices, but without attaching the electrodes. The capsules
and the free electrodes were placed together into the extraction medium in proportions
equivalent to those used to produce functional devices. Because initial trials of the
BION™ were conducted in Canada, this modification was approved by the Canadian
government with whom we consulted prior to testing (Appendix 3).
Cytotoxicity tests and a battery of genotoxicity tests were conducted. The in vitro tests
involved taking extracts of the microstimulator components and subjecting cells to these
extracts. Current standards recommend assays of genotoxicity tests covering three
different levels of effects: gene mutations, chromosomal aberrations, and DNA effects.
Thus, the following three tests were performed: the Salmonella Typhimurium (Ames)
mutagenicity test, the chromosomal aberration test, and the sister chromatid exchange
test. Short-term in vivo tests involved injecting device extracts into animals and
observing them for adverse effects to evaluate short-term intracutaneous reactivity,
systemic toxicity, and sensitization. Long-term in vivo tests conducted in collaboration
with NAmSA involved implantations of test devices into muscle in order to assess foreign
body reactions and chronic toxicity of the devices. A summary of the test results follows.
A copy of the final report of chronic toxicity trials including the histopathological analyses
from NAmSA is found in Appendix 4.
2.2.2.1.
In Vitro Tests
2.2.2.1.1. Salmonella Typhimurium Reverse Mutation Test
Test Description
This assay was conducted to evaluate whether a saline extract of the BION
microstimulators would cause a mutagenic effect on any of five histidine-dependent
mutant tester strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537,
TA1538) with and without the presence of mammalian microsome activation (rat liver S9 fraction). The plate incorporation assay of Ames et al. (1975) was used after
extraction in normal saline. Sample mutagenicity was evaluated by determining the
dose-response curve of any presumptive positive response.
Test Results
The saline test article extract was found to be non-inhibitory to growth of tester strains
TA98, TA100, TA1535, TA1537, and TA1538. Separate tubes containing 2 ml of molten
top agar supplemented with histidine-biotin solution were inoculated with 0.1 ml of
culture for each of five tester strains, and 0.1 ml of the saline extract. A 0.5 ml aliquot of
S9 homogenate simulating metabolic activation was added when necessary. The
mixture was poured across triplicate Minimal E plates. Parallel testing was also
conducted with a negative control, and four positive controls. The mean number
revertants of the triplicate test plates were compared to the mean number of revertants
of the triplicate negative control plates for each of the five tester strains employed. The
values (means) obtained for the positive controls were used as points of reference.
Under the conditions of the assay, the saline extract from the BION microstimulator
was not considered to be mutagenic to Salmonella typhimurium tester strains. The
negative and positive controls performed as expected.
2.2.2.1.2. Chromosomal Aberration Test
Test Description
This assay evaluates potential mutagenic properties which cause structural changes to
the chromosome in a mammalian cell line from the Chinese hamster ovary (CHO). The
chromosomes are examined for aberrations during metaphase of the cell cycle, with or
without mammalian chromosome activation (rat liver S-9 fraction) following the
methodology of Galloway et al. (1985).
Sample mutagenicity is confirmed by
determining a dose-response curve for any presumptive positive response.
The test article was extracted in McCoy’s 5A Medium. A monolayer of CHO cells was
exposed to the test article extract in triplicate cultures and in the presence and absence
of S9 metabolic activation. Parallel testing was also conducted with a negative and
positive control. Culture medium was used as the negative control and the positive
control was mitomycin C (MMC) in the absence of S9 and cyclophosphamide (CP) in the
presence of S9.
Test Results
Under the conditions of this assay, the extract was not considered genotoxic to Chinese
Hamster Ovary cells in the presence or absence of S9 metabolic activation. As
expected, positive controls showed significant evidence of genotoxic activity.
2.2.2.1.3. Sister Chromatid Exchange
Test Description
This assay evaluates potential mutagenic properties in device extracts that could cause
primary DNA damage in the cell. Differential staining of labeled sister chromatids is
used to identify damage. Tests are run with and without mammalian microsome
activation (rat liver S-9 fraction) according to the methodology of Galloway et al. (1985).
Potential sample mutagenicity is confirmed by constructing a dose-response curve on
any positive response.
A monolayer of CHO cells was exposed to the test article extract in triplicate cultures in
the presence and absence of S9 metabolic activation. Parallel testing was also
conducted with negative and positive controls. Culture medium was used as the
negative control and the positive control was mitomycin C (MMC) in the absence of S9
and cyclophosphamide (CP) in the presence of S9.
Test Results
Under the conditions of this assay, the test extract was not considered genotoxic to
Chinese Hamster Ovary cells in the presence or absence of S9 metabolic activation.
The negative and positive controls performed as expected.
2.2.2.1.4. Cytotoxicity Testing in the L-929 Mouse Fibroblast Cell Line
The purpose of cytotoxicity testing is to assess and measure cell damage, changes in
cell growth and changes in cellular metabolism. Two ways have been identified to
conduct these evaluations in cell cultures: tests using extracts from the material and
tests using direct contact of the material with the cultured cells. The importance of using
materials in a form as close to the final product has been emphasized by testing
guidelines. The laboratory with whom we have worked (NAmSA) recommended using a
minimum essential medium (MEM) elution method using a serum-based extraction
medium to maintain the culture. Direct contact methods were not considered to be as
sensitive or reliable as MEM methods.
Test Description
An extract of leachables from the test article was prepared using Minimum Essential
Medium (MEM). This test extract was placed onto a confluent monolayer of L-929
mouse fibroblast cells. Separate flasks were prepared for duplicate negative controls
and for a positive control (end-point titration procedure). The monolayers in both test
and negative control flasks were examined microscopically at 24, 48, and 72 hours to
determine any change in cell morphology. The monolayer in the positive control flasks
was examined at 24 hours and the result was compared to the NAmSA historical value.
Test Results
Under the conditions of this study, the MEM test extract showed no evidence of causing
cell lysis or toxicity. Negative and positive controls performed as expected.
2.2.2.2.
Short Term in vivo Tests
2.2.2.2.1. Intracutaneous Reactivity Study in the Rabbit
Irritation tests estimate the irritation potential of devices, materials and/or their extracts
using an appropriate site for implantation. Intracutaneous toxicity tests will screen for
the local toxicity of leachable materials.
Test Description
The BIONs were extracted in 0.9% Sodium Chloride USP solution and Cottonseed Oil,
NF. These extracts were evaluated for the intracutaneous reactivity in accordance with
the requirements of the International Organization of Standardization: Biological
Evaluation of Medical Devices, Part 10: Tests for Irritation and Sensitization.
A 0.2 ml dose of extract was injected by the intracutaneous route into five separate sites
on the right side of the back of each rabbit. Similarly, the corresponding reagent control
was injected on the left side of the back of each rabbit. Three rabbits were used for
each pair of extracts. The injection sites were observed immediately after injection.
Observations for erythema and edema were conducted at 24, 48, and 72 hours after
injection.
Test Results
Under the conditions of this study, there was no evidence of significant irritation or
toxicity from the extracts injected intracutaneously into rabbits.
2.2.2.2.2. Acute Systemic Toxicity Study in the Mouse
Test Description
Test articles were extracted in 0.9% Sodium Chloride USP solution and Cottonseed Oil,
NF. The extracts were evaluated for intracutaneous reactivity in accordance with the
requirements for the International Organization of Standardization: ISO 10993 Biological
Evaluation of Medical Devices, Part 11: Tests for Systemic Toxicity. A single dose of the
appropriate extract was injected by the intracutaneous route into five mice per extract by
either the intravenous or intraperitoneal route. Similarly, five mice were dosed with each
corresponding reagent control. The animals were observed immediately and at 4, 24, 48,
and 72 hours after systemic injection.
Test Results
Under the conditions of this study, there was no mortality or evidence of significant
systemic toxicity from the extracts.
2.2.2.2.3. Sensitization Study in the Guinea Pig (Maximization Method)
Test Description
A guinea pig sensitization test was conducted in accordance with the requirements of
the International Organization for Standardization, Part 10: ISO 10993 Tests for Irritation
and Sensitization. Sensitization tests estimate the potential for contact sensitization as
the result of exposure to the device, its materials or its extracts, by using an animal
model. BIONs were extracted in 0.9% Sodium Chloride (USP) and Cottenseed Oil
(NF). Each extract of the test article was injected intradermally and patched occlusively
to ten test guinea pigs (per extract) in an attempt to elicit sensitization. Following a
recovery period, the test and control animals received a challenge patch of the
appropriate test article and control vehicle. All sites were scored at 24, 48 and 72 hours
after patch removal.
Test Results
Under conditions of this study, neither saline nor cottenseed oil extracts showed
evidence of causing delayed contact sensitization in the guinea pig.
2.2.2.3.
Long-term In Vivo Tests
The object of testing was to evaluate the response of the muscle to implantation of
BIONs with respect to negative control materials. Test articles were BION
microstimulators and BION microstimulators in which the glass capsule was coated
with a thin-walled silicone sheath. The control articles were USP negative control
polyethylene rods and custom-fabricated silicone rods. The relative biocompatibilities of
test and control articles were evaluated according to three criteria: thickness of the
fibrous encapsulation, the proliferation of inflammatory cells and the appearance and
enzyme staining of muscle fibers surrounding the device. Evaluations were carried out
at spaced intervals of one month, six months and thirteen months. Data were
supplemented by observations from a series of intensively studied animals with two to
three month survival plans already reported in the literature (Cameron et al., 1998b).
A total of nine animals were implanted with three test articles and two negative control
articles. One test article was implanted in the tibialis anterior muscle whereas the others
were distributed in paraspinal muscles in accordance with conventional biocompatibility
testing protocols (e.g. ISO 10993 (ANSI/AAMI) Biological evaluation of medical devices
– Part II: Tests for systemic toxicity). Animals were monitored and evaluated at
specified time-points for changes in activity and eating patterns, changes in appearance
and abnormalities of body temperature and/or hematological status. Following animal
sacrifice, the foreign body responses were examined by removing the muscle tissue
around the device, extracting the device and bisecting the tissue block for histochemical
analysis. The animals were subjected to a systematic necropsy by a veterinary
pathologist.
Test Results
The test articles did not produce greater capsule thicknesses, inflammatory reactions or
muscle-fiber change than negative controls. In one instance, an animal was removed
prematurely from the test population because of an interuterine infection whose course
was carefully monitored by a veterinary pathologist. The condition was believed by
veterinary personnel to have pre-existed prior to device implantation and judged to be
unrelated to the implantations. The devices in this animal provoked similar foreign body
reactions to those around negative control articles, but data were excluded from the trial
according to our standard operating procedures established for animal exclusion and
removal. The other animals displayed activity levels, eating patterns and weight
changes within normal ranges for the duration of the study.
Evaluations of
hematological status and body temperature throughout the survival periods showed no
significant deviations from control values. No abnormal findings were observed at
necropsy in any of the animals completing the trial.
2.3.
Safety and Efficacy in Animals
Safety and efficacy are particularly important concerns when a device is to be implanted
into biological tissue. A series of stress, wear, environmental, and electromagnetic
compatibility, and hermeticity tests were conducted on the BION™ system components.
In each instance, the test parameters and sample size were selected in consideration of
the significance of the test with respect to product safety and performance. Samples
were evaluated before and after each test. Following each test, the characteristics of
pertinent elements were evaluated and found to be the same as the pre-test
performance output characteristics. Test descriptions and the results of each test are
described below.
2.3.1. Electromagnetic Compatibility
The shoulder coil that is worn by the study participant creates a radiofrequency magnetic
field that is used to provide power and command signals to the implanted device. One
common concern with this device and other medical devices that utilize electromagnetic
energy is exposure of the study participant to this energy. However, previous studies
have shown that radiowaves as well as other types of electromagnetic radiation are not
associated with significantly increased incidence of disease or tissue damage, even at
doses much higher than those used in the present study. For example, magnetic
resonance exposure of mouse and chick embryos did not affect the birth dates, birth
numbers, or cause abnormal development (Yip et al, 1994; Frolen et al., 1993; Wiley et
al., 1992; Margonato, et al., 1995); Exposure of adult baboons to 60Hz electromagnetic
field exposure had no effect on their performance in accomplishing a complex task (Orr
et al., 1995). To support further the literature (under the special conditions of the
specifically tuned magnetic coil in the shoulder pad), a study was conducted at Queen’s
University in Kingston, Canada to test the safety of a magnetic field used to transmit
power and data to microstimulator devices.
Test Description
Sixteen mice (8 weeks old) were randomly separated into two equal sized groups and
caged. Each cage was enclosed in a magnetic coil. The control group had an inactive
coil, whereas the experimental group had a coil that transmitted EMF radiation
continuously for the duration of the test period. The magnetic field to which the mice
were exposed was similar to that which will be used for the clinical studies: a 2MHz
sinusoid with 0.5 amperes of current through 10 turns of wire wrapped in a helical coil,
10 diameter, 15 long. Both groups of mice were fed and given water ad libitum in a
room in which air temperature was held at 23C and a light cycle of 12 hours on, 12
hours off was used. Mice were then sacrificed after 3 months of coil exposure.
Necropsies were performed to detect any ill effects due to magnetic field exposure.
Blood tests and necropsies were conducted on the mice under blinded conditions by a
non-partial veterinarian (Dr. Michael Shunk, Animal Care Services, Queen’s University
Kingston).
Test Results
blood smear tests - Mice in both groups were tested for abnormal white blood cell
counts. Counts of lymphocytes, neutrophils and eosinophils were within normal range
and did not differ significantly between the two groups.
Autopsies - All mice were subjected to an exhaustive autopsy by the certified veterinary
pathologist. Organs were examined for abnormalities. There were some variations in
organ features but their occurrence was not statistically correlated with the EMF
conditions under which they were raised, and were judged by the inspecting veterinarian
to be typical of normal variations in animal health. No tumors were observed in any of
the mice.
2.3.2. Stress Tests
Stress testing is defined as testing designed to increase the likelihood of failure by
subjecting the sample to conditions that will accelerate the occurrence of failure. In
preliminary tests, a three-point bending test was initially performed on glass capsules. A
more complicated test was subconsequently conducted to model how external forces,
such as sudden accidental impact applied to overlying soft tissues, might be conveyed to
an embedded microstimulator. A summary of the test results follows. Detailed test
results can be found in Appendix 5.
2.3.2.1.
Three-Point Bending Test
Test Description
Glass capsules of the same material and dimensions used in the BION™ encapsulation
were prepared by the Bio-Medical Engineering Unit (BMEU) at Queen’s University.
These capsules, 11,12 and 15mm in length, were subjected to a three-point bending
test, with corresponding support lengths of 7.5, 9 and 12.5 mm.
Test Results
The glass capsules were found to sustain at least 2kg of lateral force in a three-point
bending configuration along their long axis. The breaking point increased linearly with
decreasing capsule length.
2.3.2.2.
Impact Testing
Test Description
Test devices were instrumented with strain gauges and subjected to impacts from
projectiles of various shapes, weights, and velocities while padded by a typical thickness
of muscle (1 cm above, 2 cm below or the reverse) and artificial skin. The impact testing
apparatus was built around an Instron Model 1122 Universal Tester. A straight vertical
was used as a barrel to guide the impactor or missile in free-falls due to gravity over a
target. The target tissue was mounted on a calibrated loadcell. BION™ capsules were
positioned within this muscle at two depths and two horizontal locations. Missiles with
different weights and impactor sizes were dropped from various heights onto the target
tissue. Bending forces from the strain gauges on the capsules were recorded and
compared to calibrated bending forces applied in the three-point bending test.
Test Results
Test results suggested that microstimulator failure would be unlikely to occur during any
impact in vivo. Although glass is a brittle material, the symmetrical capsule geometry
and the soft tissue padding afforded by its intramuscular location make fracture of a
BION™ in situ highly unlikely. The recorded forces have been consistently below 20% of
the breaking limit even for impacts likely to cause substantial injury (e.g. 25 mm diameter
bullet weighing 1 kg dropped from 1.4 m). The highest recorded strain was about 25%
of the 2 kg breaking point in the Instron test, with most values well below 10%. The
bending forces actually decreased for devices directly under the highest energy impacts,
apparently because the muscle tissues surrounding the capsule lost mechanical integrity
before they could apply much force to the capsule. It was observed that a great deal of
tissue damage occurred in the region of impact that was not associated with the
presence of a BION™ capsule. This suggests that tissue damage to the muscle is likely
to be of much greater concern than potential damage to the microstimulators.
2.4.
Safety and Efficacy in Humans
2.4.1. Electrical Stimulation Using BIONs™ to Treat Shoulder Subluxation
Soon After Stroke
2.4.1.1.
Background
Investigational testing of the BION™ in stroke survivors suffering acute shoulder
subluxation began at Queen’s University, Kingston, Ontario, Canada, where the principal
investigators, Dr. Loeb and Dr. Richmond, were faculty members until 1999 when they
moved to academic appointments at the University of Southern California. Stephen
Bagg, M.D. is the physician conducting this trial. Dr. Bagg is an Assistant Professor in
the Department of Rehabilitation Medicine and Director of the Stroke Rehabilitation
Program at Queen’s University.
Strokes are considered to be the most important cause of adult disability in North
America, with 500,000 new cases per year in the U.S. (National Stroke Association) and
45,000 in Canada (Langton Hewer, 1990; Shuaib and Hachinski, 1991). Three-quarters
of these patients survive and half of the survivors have substantial muscle weakness
after 6 months (Gresham et al., 1979) with little chance of rehabilitation (Anderson,
1990; Bonita and Beaglehole, 1988). The most commonly affected region is the
shoulder; 80% of hemiplegic stroke patients suffer from shoulder subluxation and
associated chronic pain (Smith et al., 1980).
The mechanical integrity of the human shoulder depends largely on tension in its soft
tissue supports including the “rotator cuff” muscles and associated tendons and
ligaments. If the muscles are paralyzed, the continuous traction from the weight of the
arm stretches these soft tissues resulting in chronic subluxation and pain (Caillet, 1991;
Griffin and Reddin, 1981) with progressive loss of the normal range of motion (Andrews
and Bohannon, 1989; Joynt, 1992). The key muscles appear to be the deltoid and
supraspinatus which are normally tonically active when walking with the arm hanging
freely (Rowe, 1988). Exercises to rehabilitate the arm may actually increase shoulder
pain if these muscles remain inactive (Kumar et al., 1990). Slings interfere with
rehabilitation, provide little relief from pain and may accelerate contracture formation
(Hurd et al., 1974).
Transcutaneous electrical stimulation of the supraspinatus and posterior deltoid muscle
has been shown to be an effective, if labor intensive, treatment that reduces subluxation
and pain and improves range of motion and overall arm function (Faghri et al., 1994).
This approach is unlikely to gain widespread use because a therapist is required
to position the skin electrodes and adjust the stimulation parameters for each treatment
session. As described below, we are implanting two BIONs™ to provide stable and
selective stimulation of these muscles, enabling the study participant to self-administer
at home one or more exercise programs devised by their therapist.
2.4.1.2.
Trial Description
The study will include a total of 30 participants in a prospective, cross-over design. The
subjects are recent (typically 3-10 weeks) stroke survivors with dense hemiparalysis
involving the shoulder muscles. After giving his or her consent to participate in the
study, each study participant is randomized, with half receiving BION™ TES along with
conventional physical therapy and half receiving only conventional physical therapy.
After six weeks of BION™ treatment, the participants who received implants discontinue
stimulation for six weeks. After six weeks of conventional physical therapy, the control
subjects are offered BION™ implants and TES. Complete bilateral evaluations are
carried out before and after each 6-week treatment period. These evaluations assess
shoulder subluxation by x-ray and palpation with calipers, thickness of the implanted
muscles by ultrasonic imaging, active and passive range of motion, voluntary muscle
force, self-reporting of pain, and blood composition (white blood cell count and creatine
phosphokinase level).
BION™ implantation is performed in an examination room using aseptic technique and
local anesthesia with lidocaine at the site of insertion. Each BION™ is presterilized by
autoclaving and is tested while still in its sterile package and just prior to insertion to
confirm that it is responding to the unique address. The insertion tool is a modified 12
gauge Angiocath™ in which the stainless steel trochar has been equipped with a
connector. Electrical stimulation is delivered through the tip from a conventional clinical
stimulator to find the location where a strong twitch of the correct muscle can be
achieved with a low stimulus current. The trochar is then removed and the BION™ is
slid down the lumen of the plastic sheath and expelled by a plunger into this site as the
sheath is withdrawn. At the conclusion of the insertion procedures, weak stimulation is
applied through each BION™ to confirm its placement and functionality and to record
threshold for producing a palpable twitch. Threshold is measured and tracked at each
subsequent programming session, beginning 4-6 days after implantation and at
gradually lengthening intervals after implantation. The study participant is issued a
Personal Trainer™, a compact controller into which the clinician downloads up to three
different exercise programs and which records the times and durations of each exercise
program that the participant activated. Typically by the end of the program, study
participants are self-administering three 30-minute periods of intermittent stimulation
(5pps; 10 seconds on, 5 seconds off)
2.4.1.3.
Preliminary Results
To date, six individuals have completed the study. Three participants were
experimental subjects who received implants at the time that they entered
the study. The other three were control subjects, but two of those opted
to receive BIONs™ at the end of the control period according to our protocol
in which devices are offered to all control subjects after the initial study
period. In 2000, Richmond, et al., published the data gathered from the
clinical study of the two initial participants. Two more abstracts have
been submitted for publication in 2001, describing some of the results that
we have obtained with these subjects (Dupont et al., 2001a and 2001b).
Thresholds in individuals ranged between 1-3 mA using both percutaneous and
BION™ stimulation.
Marked fatigability in the first few days of TES
gradually resolved so that both the strength and duration of the exercise
sessions could be increased. In one experimental participant, the device
implanted in the supraspinatus failed to activate the muscle, possibly
because the device was placed inappropriately. No untoward effects were
observed in this or any of the other participants.
The two control
patients who opted to have BION™ therapy are now being followed and tested
regularly for thresholds, subluxation, and other related outcome measures
to determine if BION™ therapy will decrease their subluxation and level of
disability.
Figure 3: Subluxation Index (Dv) Graph for Each Subject
1 exp
3 cont
5 cont
20
2 exp
4 deltoid
Dv (mm)
15
10
5
0
-5
0
6
12
weeks
Figure 3. This graph depicts the difference in x-ray measurements of the affected shoulder and the non-affected shoulder
(Dv). In the two experimental subjects (solid lines no. 1 and 2), the subluxation is decreased during the 6 weeks of
stimulation (indicated by thick horizontal line). During the following 6 weeks when there is no stimulation, the subluxation
returns somewhat. For patient 4, who had only the deltoid stimulated (his supraspinatus was not stimulated), there was
some improvement of subluxation, but not as pronounced. For the two control subjects, no improvements were seen.
Figure 4: Muscle Thickness Graph
thickness (mm)
30
pre-treatment
6 wks ON
6 wks OFF
25
20
15
10
5
0
prox
dist
med
deltoid deltoid supra
subject 1
lat
supra
prox
dist
med
lat
deltoid deltoid supra supra
subject 2
Figure 4. This graph depicts the muscle thickness for experimental subjects 1 and 2. The graph shows that in general,
muscle thickness (measured at different points on the deltoid and supraspinatus muscles) increased .
2.4.2.
2.4.2.1.
Electrical Stimualtion Using BIONs™ To Treat Muscular Hypotrophy
In Individuals With Osteoarthritis
Background
This trial is being conducted in collaboration with Carlo Romano, M.D. at the Istituto
Ortopedico Gaetano Pini in Milan, Italy. Dr. Romano has worked with Drs. Loeb and
Richmond for several years on the background research and protocol development that
led to the selection of knee arthritis as the first application for BIONs™ in the area of
orthopedic rehabilitation. Arthritis of the knee is associated with muscle atrophy as both
cause and effect. Many studies have demonstrated objective clinical benefits from
exercise programs (Fisher et al., 1993a; Fisher et al., 1993b; Fisher et al., 1997a; Fisher
et al., 1997b; Hurley et al., 1998; Laprade et al., 1998; Maurer et al., 1999; O’Reilly et
al., 1999). For example, Fisher et al. (1997b) demonstrated that rehabilitation exercises
can significantly improve muscle strength (+55%), resistance to fatigue (+42%), and
contraction velocity (+34%) of the quadriceps muscle. Such strengthening improved
walking speed by 21%, reduced pain by 13% and improved daily activities by 33%
(measured with the Jette Functional Status Index – JFSI). However, exercise-based
treatment requires a lengthy and costly rehabilitation regime and total patient
cooperation. Even then, results are mixed. In fact, in the presence of arthrogenic reflex
inhibition of motoneurons, the active exercises do not produce a full return of muscle
strength even when performed consistently by the patient because the whole muscle
cannot be activated voluntarily.
Transcutaneous electrical stimulation is a well-known method for building up hypotrophic
muscle (Callaghan, 1997; Enoka, 1988; Morrissey, 1988; Pocholle et al., 1993).
Practical constraints, however, tend to limit widespread application of this technique in a
clinical setting. These include demands on caregiver time to apply electrodes and adjust
stimulation intensity, difficulty of activating deeper muscles, pain due to activation of
cutaneous afferents, and skin irritation from electrodes operated at high current levels.
Imbalance of knee muscle strength is associated with increased severity of symptoms
and poor or prolonged recovery in a variety of degenerative and post-traumatic
pathologies of the knee. Patellofemoral chondromalacia is a relatively common
condition characterized by different degrees of cartilage damage, from cartilage
softening to exposed subchondral bone and osteoarthritis. It is usually associated with
anterior persistent knee pain, especially worsened by prolonged sitting or descending
steps or hills.
Chondromalacia of the knee can be idiopathic, but it is usually associated with patellar
malalignment as a result of specific weakness of the vastus medialis muscle (Kannus &
Niittymaki, 1994; Thomee et al., 1995; Tria et al., 1992). Muscle strengthening is the
most prescribed treatment by many authors with successful results in most cases (cf.
Juhn, 1999; Laprade et al., 1998; Mirzabeigi et al., 1999). However, isolation of vastus
medialis, although recommended by different investigators, is difficult to ensure using
voluntary exercise (Mirzabeigi et al., 1999).
2.4.2.2.
Trial Description
A prospective clinical study is being conducted on subjects with chronic, stable
osteoarthritis of the knee. Each study participant acts as his or her own control because
subjects are heterogeneous in their degree of muscle wasting. We can use the
participants as their own baseline because the degree of atrophy remains stable over
time unless treated. Each subject is evaluated over a 12-week period before BIONs™
are implanted and over a 12 week period after the BIONs™ are implanted when he or
she returns to the clinic to have his or her stimulus program updated. Stimulation is then
stopped for 12 weeks and another evaluation takes place.
2.4.2.3.
Preliminary Results
Thus far, three study participants have been implanted with BIONs™. In each
participant, one BION™ was implanted near the common femoral nerve distal to the
inguinal canal and a second BION™ was implanted in the vastus medialis muscle. The
thresholds during percutaneous testing with the insertion tool and immediately following
BION™ implantation were in the range of 2-6 mA@200µs indicating successful
placement near the desired motor nerves. One of the participants reports adverse
symptoms that could be related to the use of the device. All report improvement in knee
pain and in their ability to use the knee. In one subject, the device injected in the region
of the vastus medialis did not enter the muscle fully; this device was ineffective at
stimulating the muscle, but effective muscle stimulation could be secured by stimulating
the femoral nerve. We are currently considering a modification to this experimental plan
for subsequent participants that would eliminate the placement of the second device in
the vastus medialis.
2.5.
ADVERSE INFORMATION
Because this is a novel application of the BION™ microstimulator, there are no
publications of adverse information that are relevant to an evaluation of the safety or
effectiveness of the device. Adverse symptoms are typically not reported by patients
even when the patients are thoroughly questioned about their possible concerns or
problems.
One patient in the osteoarthritis trial has reported a very modest
dysaesthesia in a cutaneous field in the thigh. This dysaesthesia may relate not to the
use of the device, but to the fact that the patient has a history of peripheral neural
dysfunction. The patient has reported that this dysaesthsia does not interfere with
activities in daily living or require medical attention or pharmaceutical intervention or
management.
Any adverse events that may arise from BION™ treatment would fall into three
categories: patient injury, events associated with surgical removal of the implanted
device, and loss of device function. The results of our studies are consistent with risk
analyses (discussed in section 5) that suggest a very low risk of any of these events
occurring.
3.
INVESTIGATIONAL PLAN