Chemistry: molecular biology and microbiology – Treatment of micro-organisms or enzymes with electrical or... – Metabolism of micro-organism enhanced
Reexamination Certificate
1998-09-18
2001-02-20
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Treatment of micro-organisms or enzymes with electrical or...
Metabolism of micro-organism enhanced
Reexamination Certificate
active
06190893
ABSTRACT:
BACKGROUND OF THE INVENTION
Tissue engineering is a field in which the principles of biology, engineering, and materials science are applied to the development of functional substitutes for damaged tissue. (See, Langer, et al., “Tissue Engineering”,
Science
, 1993, 260, 920). In general, three different strategies have been adopted for the creation of new tissue: (i) isolated cells or cell substrates, in which only those cells that supply the needed function are replaced; (ii) tissue-inducing substances, such as signal molecules and growth factors, and (iii) cells placed on or within matrices. Researchers have been interested in applying these novel techniques to find replacements for tissues such as ectodermal, endodermal, and mesodermal-derived tissue. In particular, researchers are invested the replacement of tissues in the nervous system, cornea, skin, liver, pancreas, cartilage, bone, and muscle to name a few.
One specific area of interest for the use of tissue engineering techniques is in bone regeneration and repair. Over 1 million surgical procedures in the United States each year involve bone repair. Bone defects can result from diverse causes such as trauma, birth defects and disease pathoses. Current methods rely on an adequate supply of autogenous (from a donor site) and/or allogenic (from a human cadaver) bone. However, removal of autogenous bone for the grafting procedure requires surgery at a second site and also involves blood loss, pain and increased morbidity. Furthermore, for allografts, there exists the potential for disease transmission or host rejection. Thus, the search for alternatives to autografts and allografts in bone repair and regeneration remains an important topic in medical research.
A variety of biologically compatible materials have been tested for use in bone repair. The materials include naturally occurring compounds such as tricalcium phosphate or hydroxyapatite porous ceramics (Yoshikawa et al.,
Biomed. Mater. Eng
., 1997, 7, 49; Ohgushi et al.,
J Biomed. Mat. Res
., 1990, 24, 1563), and synthetic materials including absorbable lactide and glycolide polymers (Ishaug, et al.,
J Biomed. Mater. Res
., 1997, 36, 17; Ashammakhi et al.,
Biomaterials
, 1996, 18, 3), and ceramic bioglasses (Yamamuro, T.,
Bone
-
bonding behavior and clinical use of A
-
W glass
-
ceramic, in Bone Grafts, Derivatives and Substitutes
, M. Urist, O'Connor, B. T., Burwell, R. G., Ed. 1994, Butterworth-Heinemann: Oxford U.K.). The existing technology, using biomaterials, though effective in many cases, is still beset with numerous difficulties and disadvantages. Thus, there still remains a need for improved methods in treating bone defects.
In 1953, Yasuda discovered an interesting property in bone (Yasuda, I.,
J Kyoto Med. Soc
., 1952, 4, 395). He first reported that upon mechanical deformation of bone, electricity was produced upon mechanical deformation of bone, a phenomenon known as the “piezoelectric” effect. He showed that the mechanical loading of bone induced electromagnetic potentials or fields that could alter bone metabolism and produce an increase in bone mass and/or structure (Yasuda, I.,
J Kyoto Pref Univ. Med
., 1953, 53, 325). Fukada, Becker, Bassett and others have suggested that the electrical activity observed in bone is a probable mediator of its repair and adaptive remodeling in response to mechanical loading (
FIG. 1
) (Fukada et al.,
J Phys. Soc. Japan
, 1957, 12, 1158; Becker et al., “The Bioelectric Factors of Controlling Bone Structure”, in Bone Biodynamics, R. Bourne, Ed., 1964, Little, Brown and Co.: New York; Bassett et al.,
Nature
, 1964, 204, 652). Furthermore, these authors have observed that an exogenous electrical stimulus alone can stimulate bone regeneration (Lavine et al.,
Nature
, 1969, 224, 1112; Humbury et al.,
Nature
, 1971, 231, 190; Becker et al.,
Clin. Orthop. Rel. Res
., 1977, 129, 75; Bassett et al.,
Clin. Orthop. Rel. Res
., 1977, 124, 128; Brighton et al.,
Clin. Orthop. Relat. Res
., 1977, 124, 106; Watson et al.,
Jap. J Appl. Phys
., 1978, 17, 215; Bassett et al.,
Science
, 1979, 184, 575). The early success of these experiments with direct current and electromagnetic induction finally led to widespread clinical treatments of non-union bone fractures. However, localization of the electrical stimulation, which is critical to effective treatment, still remains a challenge (Spadaro, J. A.,
Bioelectromagnetics
, 1997, 18, 193). Therefore, a system whereby one can externally control and regulate the stimulus would be extremely attractive.
Clearly, there remains a need to develop systems and methods whereby biological activities of cells, such as, but not limited to cell growth, can be stimulated by direct application of electromagnetic stimulation. This would be particularly important in applications to tissue engineering.
SUMMARY OF THE INVENTION
The concept of “tissue engineering” comes into play in the present invention for the development a system in which the biological activities of cells can be stimulated. An interesting class of synthetic polymers explored previously by Langer and co-workers as three-dimensional matrices that can take advantage of these properties are the electrically conducting or electroactive polymers. Based on their ability to respond to electrical or electromagnetic stimuli, they can act as an interface between the external and physiological environments of a connective tissue such as bone, which is capable of undergoing repair and regeneration on exposure to the same stimuli (Shastri et al., “Biomedical Applications of Electroactive Polymers”, in
Electrical and Optical Polymer Systems
, D. L. Wise, Wnek, G. E., Trantolo, D. J., Cooper, T. M., Gresser, J. D., Ed., 1998 Marcel Dekker: New York, 1031).
The present invention provides compositions, methods and systems for the stimulation of biological activities within cells by applying electromagnetic stimulation to an electroactive material, wherein the electromagnetic stimulation is coupled to the electroactive material. The present invention provides methods for the stimulation of biological activities within cells, which involves attaching or associating the desired cells to or with a surface comprising an electroactive material, and applying electromagnetic stimulation directly to the desired area. In preferred embodiments, the stimulation of biological activities within cells results from inducing one or more activities including, but not limited to, gene expression, cell growth, cell differentiation, signal transduction, membrane permeability, cell division, and cell signalling. In exemplary embodiments, the electroactive materials are either two-dimensional substrates or three-dimensional substrates comprising a matrix having at least one surface of an electroactive material.
In one preferred embodiment, the present invention provides a method for stimulating one or more biological activities of cells comprising contacting cells with an electroactive substrate, wherein the electroactive substrate already has attached thereto, or associated therewith, mammalian tissue, and subsequently applying electromagnetic radiation at the location of the electroactive substrate, wherein the electromagnetic stimulation is coupled to the electromagnetic material. In another embodiment, a composition of cells and an electroactive substrate is first provided, wherein the electroactive substrate has at least one surface of electroactive material, and wherein the cells are attached thereto or associated with the electroactive substrate. Subsequently, the electromagnetic stimulation is applied to the composition in vitro, wherein the electromagnetic stimulation is coupled to the electromagnetic material and finally the composition is contacted with mammalian tissue to effect stimulation of cell function. In yet another embodiment, a composition of cells and an electroactive substrate is first provided, wherein the cells are attached thereto or associated with the electroactive substrate. Subsequently, the composition is then contacted wi
Langer, Jr. Robert S.
Martin Ivan
Rahman Nahid
Shastri Venkatram R.
Choate Hall & Stewart
Massachusetts Institute of Technology
Weber Jon P.
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