WO2013188380A1 - Piezoelectric composites and methods of making - Google Patents

Abstract

There is a need for methods that can produce piezoelectric composites having suitable physical characteristics and also optimized electrical stimulatory properties. The present application provides piezoelectric composites, including tissue-stimulating composites, as well as methods of making such composites, that meet these needs. In embodiments, methods of making a spinal implant are provided. The methods suitably comprise preparing a thermoset, thermoplastic or thermoset/thermoplastic, or copolymer polymerizable matrix, dispersing a plurality of piezoelectric particles in the polymerizable matrix to generate dispersion, shaping the dispersion, inducing an electric polarization in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particles form chains.

Description

PIEZOELECTRIC COMPOSITES AND METHODS OF MAKING

BACKGROUND OF THE INVENTION

Field of the Invention

[1H 0I] The present application relates to piezoelectric composites comprising polymerizable matrices and piezoelectric particles dispersed therein. Suitably the composites are useful as tissue-stimulating materials., including spinal implants. The present application also relates to methods of making piezoelectric composites.

Background of the Invention

|{MH>2) Electrical stimulation has proven to be an effective therapy to increase the success rate of spinal fusions, especially in the diffkuk-to-fu.se population. However, in lis current form, it is hampered by limitations such as the need for a battery pack or a separate implantable device to provide power, and reliance on aser compliance for externally worn devices. An alternative treatment to aid In bone growth stimulation involves the use of growth factors such as bone morphogensc protein (BMP), However, studies on BMP have shown that it has a substantial risk for complication, including ectopic bone formation. The growth of bone spurs near the spinal canal is also of concern for anyone receiving this treatment. Some studies also suggest a carcinogenic effect related to the use of BMP.

|(M)031 One potential method by which electrical stimulation c n be generated is through the use of piezoelectric materials. Piezoelectric materials are a class of ferroeiectrics characterised by a net polarization, fte due to a nors- centro-symmefric crystalline structure. As a resnit, piezoelectric materials respond to stress with the generation of a net surface charge. Conversely, piezoelectric materials can be strained with the application of an electric field. Similar to high performance dielectric materials, piezoceramics are the most often used piezoelectric material, though they tend to be stiff and brittle. |Θ0Θ4] In spinas fusions, the use of such materials has generally been hampered by limitations on the size and shape of current piezoelectric structures as a result of the constraints of the snanniaelnring process, specifically, the need to pole a composite to induce a net piezoelectric behavior. This procedure requires excessively high electric field strengths that can therefore bring about material failure and limits the choice of available materials to those with a high dielectric strength. This, in turn, limits the total size that the composition can achieve. Irs the case of spinal implants., thicknesses on the order of 10-20 mm or greater are generally required, which is difficult to obtain with current methods.

SUMMARY OF PREFERRED EMBODIMENTS

[0005] Thas, there is a need for methods that can produce piezoelectric composites having suitable physical characteristics and also optimized electrical stimulatory properties.

0806! ΊΤ;£ present application provides piezoelectric composites, including tissue-stimulating composites, as well as methods of making such composites, that mee these needs.

[0TO7J In embodiments, methods of making a spinal implant are provided.

The methods suitably comprise preparing a thermoset, thermoplastic or thermose /thermoplastic, or copolymer poiymerizabie matrix, dispersing a plurality of piezoelectric particles in the polymerizabie matrix to generate a dispersion, shaping the dispersion, inducing ars electric polarization in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particles form chains as a result of the induction of the electric polarization, and curing the dispersion to generate the spinal implant.

{0008] In embodiments, the shaping comprises Injection molding, extrusion, compression molding, blow molding or thermoforraing.

| 009| Suitably, the piezoelectric particles exhibit a Perovskite crystalline structure. Exemplary piezoelectric particles include, but are not limited to, particles of barium titanate, particles of hydroxyapatite, particles of apatite, particles of lithium sulfate monohydrate, particles of sodium potassium niobaie, particles of quarts, particles of lead zirconium iitanate (PZT), particles of tartaric acid and poSy(vinyiidene di fluoride) fibers.

[00010] In embo oimenis, the inducing an electric polarization comprises applying an electric field in a direction to the shaped dispersion.

|0 0il] Suitably, the inducing an electric polarization comprises applying a hydrostatic pressure to the shaped dispersion or changing the temperature of the shaped dispersion. In embodiments, prior to the curing, the methods further comprise applying an electric field in a direction to the shaped dispersion.

[00012] Suitably applying an electric field comprises applying a field with a frequency of about 1 kHz to about 10 kHz and a field strength of about i Voljy'mm to about 1 kV mm, In additional embodiments, the applying au electric field comprises applying a field with a frequency of about 1 Hz to about 100 Hz ami a field strength of about 1 Voi.t mm to about 1 kV/rnra.

[00813] Suitably, the inducing in occurs before the applying an electric field, or the inducing in can occur after the applying an electric field, or the inducing and the applying an electric fseid occur simultaneously,

[§0014] In embodiments, the electric field is applied at the same frequency with a cyclic hydrostatic pressure,

[00015 j in suitable embodiments, the curing comprises cooling, UV curing, heat accelerated curing or compression curing the dispersion.

[00016] In exemplary embodiments, the chains have a random orientation, In other embodiments, at least about 10% of the chains are aligned to within about ±\Q degrees of the direction of the applied electric field, more suitably at least about 50% of the chains are aligned to within about ±10 degrees of the

(00017] Also provided are spinal implants prepared by the methods described herein.

[00018] ϊη embodiments, spina! implants are provided comprising a polymer matrix and a plurality of piezoelectric particles, wherein at least 40% of the piezoelectric particles are in the form of chains, and the implant is a 1-3 composite, [0dt¾i in embodiments, at least about 10% of the chains are aligned to within ±10 degrees of each other, or at least about 50% of the chains are aligned to within ±10 degrees of each other,

00 20J Suitably, the piezoelectric particles exhibit a Perovskite crystalline structure. In embodiments, the piezoelectric particles are selected from the group consisting of particles of barium titanate, particles of hydroxyapatite, particles of apatite, particles of lithium sulfate rnonohydmte, particles of sodium potassium niobate, particles of quartz, particles of lead zirconium titanate (PZT), particles of tartaric acid and poly(vinylidene difluoride) fibers.

I suitable embodiments, the implant generates a current density of between about 1 to about 250 mfcroamps/cm² when compressed.

[803)22] In embodiments, methods of making a piezoelectric composite are provided. Suitably, the methods comprise preparing a poiymerizable matrix, dispersing a plurality of piezoelectric particles in the poiymerizable matrix to generate a dispersion, shaping the dispersion, inducing an electric polarization in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particles form chains as a result of the induction of the electric polarization, and curing the dispersion.

DS0231 Suitably, the polymerizable matrix comprises a thermoset polymer, copolymer and/or monomer, a thermoplastic polymer, copolymer and/or monomer or a thermoset thermoplastic polymer or copolymer blend.

[u$02 | In exemplary embodiments, piezoelectric particles for use in the methods and compositions described herein exhibit a Perovskite crystalline structure. Suitable piezoelectric particles include, but are not limited to, particles of barium titanate, particles of hydroxyapatite, particles of apatite, particles of lithium sulfate monohydrate, particles of sodium potassium niobate, particles of quartz, particles of lead zirconium titanate (PZT), particles of tartaric acid and poly(vinyIidene difluoride) fibers.

|M825] Suitably, shaping the dispersion comprises injection molding, extrusion, compression molding, blow molding or thermoforming.

|ΜΘ2δ] In embodiments, inducing an electric polarisation comprises applying an electric field in a direction to the shaped dispersion. In other embodiments, inducing an electric polarization comprises applying a hydrostatic pressure to the shaped dispersion or changing the temperature of the shaped dispersion. In additional embodiments, an electric field can be applied to the shaped dispersion in combination with the application of the hydrostatic pressure or change in temperature. This field can be applied before, after or simultaneously with the induction of the electric polarization , In embodiments, the electric field is applied at the same frequency, and can be in phase, with a cyclic hydrostatic pressure.

[00027] in embodiments, the electric fseld has a frequency of about \ kHz to about 10 kHz and a field strength of about 1 VohVmm to about IkVoIl/mm, In other embodiments, the electric field comprises a field with a frequency of about 1 Hz to about 100 Hz and a field strength of about 1 Volt/mm to about 1 kVolt'm .

[D0028] in embodiments, the curing process comprises cooling, UV curing, heal accelerated curing or compression curing the dispersion,

[Θ0Θ2 ] Suitably, the chains that are formed in the composite have a random orientation. In other embodiments, at least about 10% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field, more suitably at least about 50% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field,

[00030] Also provided are methods of making tissue-stimulating piezoelectric composites. The methods suitably comprise preparing a iherrooset, thermoplastic, themioset thermop!astic (or copolymer) po!ymerizable matrix., dispersing a plurality of piezoelectric particles in the poiymerizable matrix to generate a dispersion, shaping the dispersion, inducing an electric polarization in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particles form chains as a result of the induction of the electric polarization, and curing the dispersion.

[001131] Also provided are piezoelectric composites and tissue-stimulating piezoelectric composites prepared by the methods described throughout.

[00832] In embodiments, piezoelectric composites comprising a polymer matrix and a plurality of piezoelectric particles are provided. Suitably at least 40% of the piezoelectric particles are in the form of chains and the composite has at least one dimension of 5 mm or greater.

[00 331 embodiments, the composites are 1-3 composites. Suitably, the composites provided herein generate a current density of between about 1 to abort 250 microamps cm² when compressed- [0S 341 In farther embodiments, the composites are 1-3 composites. Suitably, the composites provided herein possess a piezoelectric charge coefficient of the composite between 1% and 100% of the bulk piezoelectric charge coefficient from which the composite is created.

[00O35J Suitably, the composites provided herein possess a dielectric constant of the composite between 1% and 100% of the bulk dielectric constant of the poSymenzabie matrix from which the composite is created,

f@¾036] Suitably, the composites provided herein possess a piezoelectric voltage constant g of the composite between 1 % and 1 .000% of the bulk piezoelectric voltage coefficient from which the composite is created.

|$O037] Also provided are tissue-stimulating piezoelectric composites comprising a polymer matrix and a plurality of piezoelectric particles.

Suitably, at least 40% of the piezoelectric particles are in the form of chains, and the composite is a 1-3 composite.

[8§038] Further embodiments;, features, and advantages of the embodiments,, as well as the structure and operation of the various embodiments, are described i detail below with reference to accompanying drawings,

BRIEF DESCRIPTION OF THE FIGURES

[ΘΦ039] FIGs. 1A and I B show representations of 0-3 and 1 -3 structured composites, respectively.

[©§046] FIGs. 2A and 2B show an exemplary method of making the piezoelectric composites described berein.

[00041] FIGs. 3A and 3B show representations of dielectric force (3A) on particles and piezoelectric force (3B) on particles, respectively. WS421 FIG, 4 A shows an exemplary manufacturing set-up for use with dieiectrophoretie (DBF) formation of piezoelectric composites described herein,

00043] FIG. 4B shows an exemplary manufacturing set-up for use with piezoeSeeirophoretic (PEP) formation of piezoelectric composites described herein.

[WI44] FIG, 5 shows the piezoelectric charge coefficient for 0-3 and 1 -3 structure composites in accordance with embodiments described herein,

[l? Mi4$J FIG, 6 shows a piezoelectric composite circuit model

[08(146] FTC, 7 shows a lumped parameters model of a mechanical system of the circuit model.

FIG. 8 shows model results for peak power versus thickness,

[W048] FIG. 9 shows model results for peak power versus cross-sectional area.

FIG. 10 shows model results for peak power versus fiber aspect ratio.

[8S6S8 FIG, 1 1 shows niodei results or peak power versus volume fraction of the fibers and load resistance for a set implant geometry,

|(NM)SIJ FIG. 12 shows model results for peak power versus load resistance for

PZT and BaTiG

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 0Θ52] It should be appreciated that the particular implementations shown and described herein are examples and are not intended to otherwise hmit the scope of the applicatio in any way,

[®W53| The published patents, patent applications, websites, company names, and scientific literature referred to herein are hereby incorporated by reference in their entireties to the same extent as if each was specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter. Likewise, any conflict between an art- understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter.

[tM>054J As used in this specification, the singular forms "a," " n" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. The term "about" Is used herein to mean approximately, in the region of, roughly, or around, When the term "about" Is used in conjunction with a numerical range, it modifies ihat range by extending the boundaries above and below the numerical values set forth, Irs general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%.

[0#§5SJ Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present application pertains, unless otherwise defined, Reference is made herein to various methodologies and materials known to those of ordinary skill in the art,

[W 5<5J Composite matrices with 0-3 connectivity 102 are typically comprised of particles 106 randomly dispersed within a matrix 104 (FIG. iA). The matrix 104 is connected to itself in all three spatial directions, while the particles 306 lack contact. As such, effective medium (EM) theory portrays the hulk, or apparent properties of these composites as isotropic. Manufacturing a 0-3 composite is a straightforward process that entails mixing small particle inclusions into a matrix until evenly dispersed. These composites are simple to manufacture in large quantities, typically at low cost.

|W S7] Orthotopic or transversely isotropic behavior can be induced in a material by inducing structural organization, such as 1 -3 connectivity (FIG 1 B), There are several methods of creating 1 -3 composites, one example includes watering a solid material into rod-like 108 structures, and backfilling the voids with the i X&ndsd material. Others entail weaving fibers 108 through a senii-poro s matrix or manually aligning long fibers 108 and then tilling the surrounding area with the composite matrix 104, These techniques result in the structures 108 forming continuous columns that span the thickness of the composite. [iDOSgj While there can be large increases in composite properties by utilizing 1 -3 composites, they typically entail 'brute force^* manufacturing techniques, and can be quite costly, labor intensive, and time consuming to produce. Nonuniform electric fields can be used to structure particles via the dielectrophoretie (DEF) force, The DEP force is based upon the surface charges induced on dielectric particles in an electric field, and the interactions between the polarized particles and the applied electric fields {FIG 3A), Structured 1-3 composites are created by utilizing the DEP force while the matrix material, is still fluid. While the inclusions are still mobile, the DEP force structures them into column-like structures, where they are held until the composite matrix has solidified. Once completed, this technique successfully creates 1 -3 structured composites with manufacturing techniques similar to those for 0-3 materials.

As described herein, methods are provided that utilise the piezoelectric nature of particles to generate composites with 1-3 connectivity. This is suitably carried out by utilizing piezoelectrophoresis (PEP). The PEP force is analogous to the DEP force, however, utilization of PEP is accompanied by the added benefit of obviating the need to pole the specimens prior to use (FIG 3B). By eliminating the need to apply a large electric field to the sample to induce net piezoelectricity, this technique allows the creation of large scale piezoelectric materials, furthermore, it allows the use of new matrix materials, previously infe&sible due to low dielectric strengths.

[00060] Though not wishing to be bound by theory, piezoelectrophoresis (PEP) relies upon the assertion that the application of hydrostatic pressure (or temperature change) to a piezoelectric particles (e.g., a sphere, fiber_s rod, etc.) generates an electric potential equivalent to the induced potential of a dielectric particle in an electric field. This results in the ability of piezoelectric particles to experience an interparticle force analogous to the DEP force, but in the absence of an externally applied electric field. This PEP force is instead attributed to a stimulus that results in the generation of charge on the particle, such as hydrostatic pressure. As a note, any other stimulus that generates charge on a piezoelectric element is capable of producing this effect (e,g. - 1 Θ ~

temporally variant temperature via the pyroelectric effect (heating or cooling), somcation, a lication of x-ray energy, etc.).

[0(MM»lj An externally applied electric field that Is applied at the same frequency with a cyclic hydrostatic pressure can result in the creation of "chains" and 1 -3 structured composites. This field care be applied in phase or out of phase, depending on the materials utilized. Also, as the PEP torque causes the particles to align their net moment with the electric field, this can also result in the formation of net piezoelectric 1-3 structured composites without the need for an externally applied electric field during a standard poling procedure. If a cyclic hydrostatic pressure is applied without the addition of an external electric field, composites with 3-3 connectivity can also be created, exhibiting an increase in dielectric, piezoelectric, and mechanics! properties compared to 0-3 composites.

[θ@θ&£| As described in FIGs 2A and 28, irs embodiments, methods of maki ng a piezoelectric composite are provided. As used herein, a "composite" means a material comprising two or more components mixed or dispersed together. As used herein, a "piezoelectric" is a material that is capable of generating a voltage when a mechanical force is applied to the material.

[O0S63J The methods described herein suitably comprise preparing a polymerizabie matrix 202. As used herein, "a polymerizabie matrix" means a composition comprising monomers, polymers (two or more repeating structural units) or mixtures of monomers and polymers, or copolymers that can form a homogeneous or heterogeneous bulk composition when polymerized.

©0064] A plurality of piezoelectric particles 204 is dispersed in the polymerizabie matrix to generate a dispersion 205, As used herein, "plurality⁵' refers to 2 or more, suitably 5 or more, 10 or more, 50 or more, 100 or more, 500 or more, 1000 or more, etc., of an item, for example piezoelectric particles. The piezoelectric particles are dispersed in the matrixes via any suitable method, including mixing, stirring, folding or otherwise integrating the piezoelectric particles in the matrix so as to generate a fairly uniform mixture of the particles in the matrix. [08065] The dispersion 205 Is then shaped 206, As used herein, "shaped" or "shaping" refers to a mechanical or physical process by which a matrix (or dispersion) is changed to a desired form. "Shaping" can also include simply placing a matrix into a desired container or receptacle, thereby providing it with a maintained shape or form, ft should be noted thai the shaped form is not necessarily the final form, as additional processing (e.g., machining, forming, etc.) can be completed on the final, cured composite (see below). The act of shaping the dispersion for use in the methods described herein is primarily to give some initial structure to the dispersion prior to further processing. A rigid or specific shape is not required.

[ti @66] An electric polarization 302 (see FIG. 3A and 3B) is then induced in the piezoelectric particles 204 in the shaped dispersion. Suitably, at least 40% of the piezoelectric particles 204 form chains 212 as a result of the induction of the electric polarization. As used herein "chain" means 5 (five) or more piezoelectric particles connected to one another in a linear or semi-linear manner, i.e., piezoelectric particles at the ends of a chain are not connected to other piezoelectric particles in the same chain so as to form a loop. As wsed herein '"columns" of piezoelectric particles are suitably formed by the stacking or aligning of more than one chain.

[#§0671 The dispersion is then cured to create a piezoelectric composite 214.

'The induction of the electric polarization is suitably maintained hi the shaped dispersion until the matrix is fully cured, so as to keep the chain formation until the matrix is solidified.

f®0§68] As used herein "connected" or "connectivity" when referring to piezoelectric particles, means that the pariicies are within about 25% of a particle radius of one another. Suitably, the radius of the largest particle of the population of piezoelectric particles is used in determining if particles are connected. As used herein "radius" refers to the smallest particle aspect, and is not meant to be limited only to spherical particles, but is also applicable to fibers, rods, and other particle shapes. Connectivity between the particles is used to differentiate the situation where an electric polarization is created in the particles, but particles do not come to within about 25% of a particle radius of one another in a matrix materia.!, but instead, remain dispersed within the matrix.

[00069] Chain formation requires connectivity or connection between particles in order to form the particles into chains. In embodiments, connected particles are within at least about 25%, at least about 20%, at least about 13%, at least about 10%, at least about 5% or at least about 1% of a particle radius of one another.

f@0¾7G] In embodiments, at least about 40% of the piezoelectric particles 2Q4 form chains 212 as a result of the induction of the electric polarization, more suitably at least about 50%, at least about 55%, at least about 60% at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%» of the piezoelectric particles 204 form chains 212 as a result of the induction of the electric polarization.

[0$8?I] Suitably, the chains are aligned with one another. As used herein "aligned" Is used to me n that the chains comprising the piezoelectric particles are oriented to within about ÷10 degrees of each other. In embodiments, the chains comprising the piezoelectric particles are oriented to within about -t-20 degrees of each other, more suitably to with within about ±15 degrees of each other, or within about ±10 degrees of each other or within about ±5 degrees of each other.

[0W72J lu exemplary embodiments, the monomers and/or polymers or copolymers of the poiymerizable matrix 202 comprise a thermoset polymer, copolymer and/or monomer, a thermoplastic polymer, copolymer and/or monomer; or a thermoset thermopiastic polymer or copolymer blend. Exemplary thermoset and thermoplastic polymers, copolymers and monomers are well known In the art, and include for example, polymers, copolymers and monomers of poly(viny!ideiie difluoride) {FVDF}, poiy(urethane), various epoxies <e.g„ ΕΡΟ-ΊΈΚ* 302-3M; EPOXY TECHNOLOGY, INC, Billerica, MA), polyethylene}, polystyrene}, poly(methyl iuefhacryiate) (PMMA), poiy(ether ether ketone) (PEEK), poly(aryletherketone) (PAEK), etc. [000731 Suitably, piezoelectric particles 204 for use in the composites described herein exhibit a Perovskite crystalline structure, i.e., the same type of crystal structure as calcium titanium oxide (CaTSOa). In embodiments, suitable piezoelectric particles include but are not limited to, particles of barium titanate, particles of hydrox apatite, particles of apatite, particles of lithium sulfate monohydrate, particles of sodium potassium niobate, particles of quartz, particles of lead zirconium titanate (PZT), particles of tartaric acid and polyvinylidene difluoride fibers. Other piezoelectric, particles known in the art can also be used in the composites described herein. Suitably, a single type of piezoelectric particle is used in the composites and methods of making the composites, though in other embodiments, mixtures of different types or classes of piezoelectric particles can also be used, in embodiments, the piezoelectric particles are on the order of less than about 1000 η¾ i size, suitably less than about 750 μβη in size, suitably less than about 500 pm in size, suitably less than about 100 in size, less than about 10 μηι, less thau about 1 um_} less than about 500 nm, or less than about 100 nm in size. As used herein "particle" includes any shape or configuration of material including spheres, fibers, angular shapes, rods, pieces or fragments of materials, flakes, shavings, chips, etc.

(Θ0074| Exemplary methods of shaping 206 the dispersions comprising the piezoelectric particles and polymerizable matrix include, but are not limited to, injection molding, extrusion, compression molding, blow molding or thenriofbrming. Other suitable shaping methods can also be used. In other embodiments, the dispersion can simply be placed in a suitable container or other receptacle to hold the dispersion while the various other steps of the methods described herein are carried out.

[0007S| in embodiments, inducing an electric polarization may comprise applying an electric field 210 in a direction to the shaped dispersion. Suitably, the electric field is applied in the direction (or perpendicular to the direction to account for negative dielectrophoresis) in which it is desired that resulting chains are to align. As shown in FIG. 3A, application of an electric field results in the induction of an electric polarization 302 in the particles. This effect is classically known as (^electrophoresis (DEP) as described herein.

|0® 76] Suitably, the electric field applied in such embodiments has a frequency of about 1 kHz to about 10 kHz and field strength of about 1 Volt/nun to about ikVo It/mm. For example, for DEP, a electric field having a frequency about 1 kHz to about 2 kHz, about 2 kHz to about 3 kHz, about 3 kHz to about 4 kHz, about 4 kHz to about 5 kHz, about 5 kHz to about 6 kHz, about 6kHz to about 7 kHz, about 7 kHz to about 8 kHz, about 8 kHz to about 9 kHz, about 9 kHz to about 10 kHz, or any otber range or value within these ranges cart be utifeed. in em odiments, such electric fields will have a field strength of about I Volt/mm to about 500 Volt/mm, about 50 Volt/mm to about 500 Volt/mm, about 100 Volt/mm to about 500 Volt/mm, about 100 Volt/mm to about 400 Volt/mm, about 100 Volt/mm to about 300 Voit/mm, or about 200 Voit/mm to about 300 Volt/mm, as well as any range or value within these ranges. Suitably, the electric field is applied as a sine wave having the characteristics described herein, though other wave shapes, including square waves, can be used.

f§0077] In further embodiments, Inducing an electric polarization suitably comprises applying a hydrostatic pressure 208 to the shaped dispersion or can comprise changing the temperature of the shaped dispersion, resulting piezoeiectrophoresis. As demonstrated in FIG. 3B, piezoeiectrophoresis (PEP) suitably results in both the formation of chains 212 of piezoelectric particles, while also alignment of dipoles 302 of the particles.

[0 078| Application of hydrostatic pressure 208 suitably comprises application of a sine wave of about 50 pounds per square inch (psi) to about 5000 psi with a frequency of about 0.1 Hz to about 200 GHz. In exemplary embodiments, the sine wave cars have a pressure of about 1 0 psi to about 2000 psi, or about 100 psi to about 1000 psi, or about 500 psi to about 1000 psi, or about 500 psi, about 600 psi, about 700 psi, about S00 psi, about 900 psi or about 1000 psi. Suitable frequencies include about 1 Hz to about 200 GFIz, about 1 Hz to about 1 0 GHz, about 1 Hz to about 1 GHz, about 1 Hz to about 500 MHz, about 1 Hz to about 100 MHz, about i Hz to about I MHz, about 1 Hz to about 500 Hz, shout 1 Hz to about 50 Hz, about 1 Hz to about 40 Hz, about 1 Hz to about 20 H¾ about 1 Hz, about 2 Hz, about 3 Hz, about 4 Hz, about 5 Hi, about 6 Hz, about 7 Hz, abosit 8 Hz, about 9 Hz, about 10 Hz, about 11 Hz, about 12 Hz, about 13 Hz, about 14 Hz, about 15 Hz, about 16 Hz, about 17 Hz, about 18 Hz, about 19 Hz or about 20 Hz, Other wave shapes. Including square waves having the characteristics noted above, can also be used.

[000791 As discussed herein, by eliminating the need to apply a large electric field (e.g., on the order of 10 kV/min or larger) to the sample to induce net piezoelectricity and "pole" the material, the methods described throughout allow for the production of materials having larger sizes and more freedom In shape and morphology of the final product tbereby enabling more diverse uses for the composites. Thus, in embodiments, the induction of an electric polarization suitably does not include the application of an electric field, ftMWSSJ In additional embodiments, though, an electric field ca be applied in a direction to the shaped dispersion in combination with the application of the hydrostatic pressure or the change in temperature to induce the electric polarisation. In such embodiments, a low-level electric field can help to further align the chains that form as a result of the PEP. In embodiments, this low level electric field can be applied with a frequency of about 1 Hz to about 100 Hz and a field strength of about I Volt/mm to about 1 kVoli/mm, For example, an electric field having a frequency about I Hz to about 75 f¾ about 1 Hz to about 50 Hz, about 1 Hz to about 40 Hz, about ! Hz to about 30 Hz, about 1 Hz to ahout 20 Hz, about 1 Hz to about 10 kHz, about S Hz, about Hz, about 3 ¾ about 4 Hz, about 5 Hz, about 6 Hz, about ? Hz, about 8 Hz, about 9 Hz, about 10 Hz, about 1 1 Hz, ahout 12 Hz, about 13 Hz, about 14 Hz, about 15 Hz, about 16 Hz, about 17 Hz, about 18 Hz, about 19 Hz, about 20 Hz. or any other range o value within these ranges can be utilized. In embodiments, such electric fields wit! have a field strength of about 1 Volt/mm to about 1000 Volt/mm, about 1 Volt/mm to about 500 Volt/mm, about 50 Volt/mm to about 500 Volt/mm, about 100 Volt/mm to about 500 Volt/mm, about 100 Volt/mm to about 400 Volt/mm, ahout S00 Volt/mm to about 300 Yolt mm, or about 200 Volt/nun to about 300 Volt/mm, as well as any range or value within these ranges.

@0 Si] In suitable embodiments, when the methods comprise inducing a electric polarization via the application of a hydrostatic pressure or a change in temperature, as well as the application of an electric field,, the induction of the electric polarization and the application of the electric field can occur in any manner. For example, the induction of the electric polarization can occur before applying an electric field or the induction of the electric polarization can occur after the application of the electric field, ϊη further embodiments, the induction of the electric polarization and the application of the electric field suitably occur simultaneously, i.e., the application of the hydrostatic pressure or temperature change occurs at the same tim as the plication of the electric field, for example both take place together or within seconds or minutes of each other.

[00082] in suitable embodiments, an electric field is applied ai the same frequency with a cyclic hydrostatic pressure in the methods. The field can he in phase or out of phase with the hydrostatic pressure, depending on the materials utilized. When used in phase, the frequency of the electric field and the frequency of the hydrostatic pressure are applied so that the maximum amplitude of the cycle of each is reached at approximately the same time, thereby resulting in an in-phase application. The cycles can also be phase offset to account for losses in the particles and matrix that can cause a phase lag or gain between the polarization inducing stimulus and the polarisation itself

[00083] Exemplary methods of curing the polymerizable matrices so as to form the fmal composite are known in the art, and include, but are not limited to, cooling, UV curing, beat accelerated curing or compression curing of the dispersion.

[01)084] In embodiments, the chains of piezoelectric particles produced in the composites prepared according to the methods described herein have a random orientation. However, in further embodiments, suitably at least about 10% of the chains are aligned to within about ±10 degrees of each other. In ftsrther emhodiments, suitably at least about 10% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field. This electric field cm be either the electric fkSd applied daring DEP to form the chains, or the electric field applied during PEP to urther align the chains,

[§§885J More suitably at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the chains are aligned to within about ±10 degrees of each other and/or of the direction of the applied electric field. More suitably, the chains are aligned to within about ±5 degrees of each other, or suitably with about ±5 degrees of the direction of each other and/or the applied electric field.

[0O686J it is well within the level of those skilled in the art to determine the direction of chain alignment and its orientation with respect to an applied electric field,

[00087] In further embodiments, methods of making a tissue-stimulating piezoelectric composite are provided. As used herein, a "tissue-stimulating" composite as described throughout is suitably implanted or otherwise introduced into a patient so as to provide electric stimulation to a tissue of a patient when the composite is placed under any stress or strain, including transverse shear, bending, torsion, twisting,, compression or tension, Exemplary tissues include, but are not limited to, bone, muscle, cartilage, tendons and organs (e,g., brain, heart, lungs). Suitably, the patients are mammals, including humans, dogs, cats, mice, rats, monkeys, etc.

[00 8SJ In embodiments, the tissue-stimulating piezoelectric composites are bone-stimulating composites, including spinal implants for spinal fusion. The electric stimulation produced by the composites aids in stimulation of bone growth and osseointegration of the composite,

00 8 ! In suitable embodiments, tissue-stimulating piezoelectric composites are prepared by preparing a thermoset, thermoplastic, thermoset/thermoplastic or copolymer polymerizabk rnairix. A plurality of piezoelectric particles is dispersed in the polymerlzable matrix to generate a dispersion. The dispersion is then shaped. f®0S9OJ An electric polarization is induced in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particles form chains as a result of the induction of the electric polarization. The dispersion is cured to form the composite.

[W091] Exemplary methods of shaping the dispersion are described herein or otherwise known in the art, and include injection molding, extrusion, compression molding, blow molding or thermotormmg,

f®§892] Exemplar}' piezoelectric particles include particles exhibiting a Ferovskite crystalline structure, Suitable particles include particles of barium titanate, particles of hydroxyapatite, particles of apatite, particles of iithium sulfate monohydrate, particles of sodium potassium rnohate, particles of quartz, particles of lead zirconium titanate (PZT), particles of tartaric acid and poly(vmylidene dii!uoride) fibers.

ΘΘ893] As described herein, in suitable embodiments, an electric polarization is induced by applying an electric field in a direction to the shaped dispersion, in additional embodiments, an electric polarization is induced by applying a hydrostatic pressure to the shaped dispersion or changing the temperature of the shaped dispersion, in such embodiments, an electric field can also be applied in a direction to the shaped dispersion. Exemplary frequencies and field strengths of the electric fields for use in the methods are described throughout,

[§S0 4| As described herein, in suitable embodiments, when the methods comprise inducing an electric polarization via the application of a hydrostatic pressure or a change in temperature, as well as the application of an electric field, the order of the induction of the electric polarization and the application of the electric field can occur in any manner. For example, the induction of the electric polarization can occur before the applying an electric field, or the induction of the electric polarization can occur after the application of the electric field. In further embodiments, the induction of the electric polarization and the application of the electric field suitably occur simultaneously, i.e., the application of the hydrostatic pressure or temperature change occurs at the same time as the application of the electric field, for example both take place together or within seconds or minutes of each other. Suitably, the electric field is applied at the same frequency with a cyclic hydrostatic pressure. The field can he in phase or out of phase with the pressure depending on the type of materials utilized.

[Θ0Φ95] Exemplary methods of curing the polymenzable matrix so as to form the final composite are known in the art, and include, but are not limited to, cooling, UV curing, heat accelerated curing or compression curing of the dispersion,

[ΘΘ096] In embodiments, the chains of piezoelectric particles produced in the composites prepared according to the methods described herein have a random orientation. However, in further embodiments, suitably at least about 10% of the chains are aligned to within about ±10 degrees of each other, in further embodiments, suitably at least about 10% of the chains are aligned to within about ±10 degrees of the direction of the applied electric fseid. This electric field can be either the electric field applied during DEP to form the chains, or the electric field applied during PEP to further align the chains.

[f> ?| In embodiments, piezoelectric composites prepared by the methods described throughout are also provided. Also provided are tissue-stimulating piezoelectric composites prepared by the methods described herein.

[§ΘΘ 8 in exemplary embodiments, piezoelectric composites comprising a polymer matrix and a plurality of piezoelectric particles are provided. Suitably, in the composites, at least 40% of the piezoelectric particles are in the form of chains. In embodiments, the composites have at least one dimension of 0.5 mm or greater, suitably at least one dimension of I mm or greater, or at least 5 mm or greater.

[00099] While m embodiments, the chains that are present in the composites have a random orientation, suitably at least about 10% of the chains are aligned to within ±10 degrees of each other.

[@80I0liJ More suitably at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the chains are aligned to within about ±10 degrees of each other. More suitably, the chains are aligned to within about ±5 degrees of each other.

§80181] Suitably, the composites provided herein and prepared by the disclosed methods are 1 -3 composites, for example as illustrated an FIG, IB,

M 182] As described herein, suitably the polymer is a thermosel polymer, a thermoplastic polymer or a thermoset mermopiastic polymer or copolymer blend. Exemplary polymers are described herein or otherwise known in the art. Suitably, the polymer is a PVDF polymer,

000103] As described throughout, exemplary piezoelectric particles for use in the compositions exhibit a Perovskite crystalline structure. Suitable piezoelectric particles include, but are not limited to, particles of barium titanate, particles of hydroxyapaiite, particles of apatite, particles of lithium sulfate raonohydrate, particles of sodium potassium mohate, particles of quartz, particles of lead zirconium iitanaie (PZT), particles of tartaric acid and poly(vinyIidene difluori e) fibers.

000104] Suitably, when stressed or strained, including transverse shear, bending, torsion, twisting, compression or tension, the composites described herein generate a current density of between about 1 microarnps/em² to about I amp/cm². More suitably the composites generate a current density between about 1 microamps/cm² to about 500 microamps/cm², about 1 mieroamps cm²io about 400 miercamps/cm², about 1 microamps/cm² to about 300 microamps/cm", about 1 mieroamps/cm²to about 250 microamps/cm², about I rmcroamps/euAo about 200 mieroanips/crr , about 1 microamps em ¾ about I SO microamps/em², about 1 microamps/cm" to about 100 microarrrps/c ^ about 1 microamps/em² to about 90 microamps cm², about 1 microamps/cm ¾o about 80 microamps/cm''; about 1 microamps/em² to about 70 mieroamps/cns² about 1 mieroamps/cn to about 60 microamps/cm², about 1 microarrms/cm² to about 50 microamps cm'¹, about 1 microamps/cm² to about 30 microamps em², about 10 niieroarnps/c ², about 20 microamps/cm², about 30 microamps/cm², about 40 mJcroamps/cm², about 50 microamps/em², about 60 microamps/cm², about 70 microamps cm², about 80 microamps/cm , about 90 microamps/cm², or about 100 microamps/cm². - 2? -

Suitably, the current density is a constant direct current density and the electri potential of the composites are negative.

Suitably, the composites have at least one dimension of 0,5 mm or greater, suitably at least one dimension of 1 mm or greater, or at least one dimension of about 5 mm or greater, or at least one dimension of about 10 mm or greater, or about 20 mm or greater, about 30 mm or greater, about 40 mm or greater, about 50 mm OF greater, about 60 mm or greater, about 70 mm or greater, about SO mm or greater, about 90 mm or greater, or about 100 mm or greater. While any dimension rid shape of composite cars be generated using the methods described, an advantage of the methods provided herein is that composites having at ieast one dimension greater than about 0,5 mm or about 1 mm or about 10 mm can readily be generated, as compared to other methods of generating piezoelectric composites where the materials are limited in size,

|000186J Also provided are methods of preparing piezoelectric composites.

Including tissue-stimulating piezoelectric composites, such as spinal implants, that are made via physical alignment of fibers in a relatively non~eondactive polymer matrix to form a 1-3 piezoelectric composite structure. Such 1-3 piezoelectric composites may have different characteristics as compared to structured 1-3 composite created using the DEP force, as described herein, in terms of toughness, fracture properties, and ease of manufacturing. Examples of suitable piezoelectric particles (i.e., fibers) are described herein, as are suitable polymeric matrices. Suitably, alignment of the fibers in these embodiments comprises physically moving the fibers into the desired position prior to curing or other manufacturing of the composite,

|Θ0©1©7| Also provided herein are tissue-stimulating piezoelectric composites.

Suitable composites comprise a polymer matrix and a plurality of piezoelectric particles, wherein at least 40% of the piezoelectric particles are in the form of chains, and the composite is a 1-3 composite.

|θ$βί Θ&1 As described herein, at least about i 0% of the chains are oriented within ±10 degrees of each other, more suitably at least about 50% of the chains are orien ted within ÷-10 degrees of each other. |CS iI09| la embodiments, the piezoelectric particles exhibit a Perovskite crystalline structure. Suitable piezoelectric particles include but are not limited to particles of barium tiianate, particles of hydroxyapatite, particles of apatite, particles of lithium sulfate monohydrate, particles of sodium potassium niohate, particles of quartz, particles of lead zirconium titanate (PZT), particles of tartaric acid and polyivinylidene diiluoride) fibers.

[θ$0Η0] In suitable embodiments, the tissue-stimulating piezoelectric composites generate a current density of between about 1 microamp cm" to about 250 microamps/em² when compressed. This current density is ideally provided to increase tissue healing, e.g., the rate of bone fusion. As the piezoelectric composites described herein generate current density simply in response to pressure, no additional power source is required.

[§00111] in further embodiments, the composites, including tissue-stimulating piezoelectric composites, are 1 -3 composites. Suitably, the composites provided herein possess a piezoelectric charge coefficient dys of the composite between 1% and 100% of the bulk piezoelectric charge coefficient from which the composite is created.

[0Θ Π2] Suitably, the composites provided herein possess a dielectric constant s¾3 of the composite between 1% and 300% of the bulk dielectric constant of the filler material from which the composite is created,

[dSOlISJ These ranges are functions of several variables that can be altered between composites. As the composite material approaches a 100% volume fraction of pieaoelectric particles, the properties approach the values of the bulk piezoelectric material. In fee embodiments* tire volume fractions are often below 50%. Another key factor these properties depend on is the aspect ratio of the piezoelectric particies. if the aspect ratio is above 30, suitably above 100, then a composite with only a 30% volume fraction of fibers suitably possesses a close to 1 0% of the bulk material, if the aspect ratio is closer to 10, then for a 30% volume fraction, the dj3 would be much closer to 25% of the bulk material value, |0@βϋ4] This same justification holds for the dielectric constant, except that there is a fairly linear relationship between dielectric constant and volume fraction,

[0IMI115] Suitably after curing, the piezoelectric composites are further shaped or molded into their desired final shape, In the case of tissue-stimulating composites, these Final shapes will be determined by the final in-patient use, taking into account patient anatomy, size requirements and ultimate use.

[CNMH16] In embodiments, the tissue-stimulating piezoelectric composites can further comprise a coating on their surface, eg,, a polymer coating or shell, to facilitate biocornpatibilify, or in some cases a coating to deliver a desirable compound or drag to the tissue. For example, a coating such as hydroxyapatite or other bone growth stimulant, drug, or resorbable scaffold polymers such as FLA (poiylactie acid) or PLLA (po!y-L-iaet!de) or PGA. (polyglycoiie acid) or antibiotics or norsrescrbable coatings such as poiy(ether ether ketone) (PEEK), poly(aryleiherkeptone) (PEAK) or other suitable materials, can be coated on the composites.

[CN HIT] !n embodiments, the piezoelectric composites are provided with an insulator which may be made of ultra high weight polyethylene or titanium oxide or any other suitable non-conductive non-toxic biocompatible materia!. The insulator can be provided on the piezoelectric element but not where a tissue-interface is desired (i.e., contact with a tissue), The conductive material can be a commercially available biocompatible epoxy composition or it can be thin layer of a precious metal such as gold or silver, or other metals such as titanium and its alloys, tantalum or cobalt chromium alloys.

[δθθΠ§1 Exemplary tissue-stimulating composites that can be produced according to the methods provided herein include bone plates, bone screws, boue implants, spinal implants_* etc,

[00 119] In embodiments, the tissue-stimulating composites described herein are strain coupled to bone or other body tissue so as to generate charge as the tissue undergoes strain, and the generated charge is applied via electrodes to a region where it Is desired to stimulate a tissue, e.g., bone growth (see, e.g., U.S. Patent No. 6, 143,035, the entire disclosure of which is incorporated by reference herein in its entirety for all purposes), in embodiments, the composites described herein can be attached by pins or bone screws to a bone and the poles of the piezoelectric element are connected via leads to carry the charge remotely and couple the charge to promote healing.

[8W12t)] Thus, the strains from the natural loading of the tissue (e,g, bone) are coupled into the piezoelectric composites and generate charge across the poles of that composite which creates a current flow.

[ e©121] In general, the direction of current flow created by the material will be alternating, dependent on whether the implant is being loaded, or unloaded (e.g., by the patient). Suitably, the direction of current flow is controlled through the use of a rectification circuit attached to the device prior to use, including implantation in a patient. Further circuitry can be involved to condition the signal, store and deliver excess energy, and power additional features or functions of the device (i.e. enabling telemonltoring, lab on a chip devices, etc).

0t)122| When an implant (e.g., a spinal implant) is loaded, it may generate a positive charge on top, and negative on the bottom. However, when unloaded, it will then generate a negative charge on top, and positive on the bottom. This implant will operate suitably under cyclic loading (i.e. walking), as such, an AC current would be created, in order to deliver DC stimulation, as that is the most effective form of electrical stimulation, the AC signal must be rectified before delivery to the patient.

[0W123 In general, the direction of current flow induced in a patient is dependent on the pole orientation of the piezoelectric composite and the direction of strain loading, e.g., tensile or compressive strain, applied to the composite. Suitably, the direction of current flow is selected during manufacture and configuration of appropriate circuitry so that implantation of the composite produces the desired effect, e.g., enhanced hone growth effects.

[0SO124] In addition to use as tissue-stimulating composites, the piezoelectric composites described herein can suitably he used in any number of additional applications and configurations, Methods of shaping, forming or otherwise preparing the composites described herein to be utilized in such applications are well within the level of one of ordinary skill is ihe art of the various applications.

[000125] For example, piezoelectric composites described herein can be utilized in the following;

[000126] Carbon black impregnated PMMA or other polymers to generate a raatrk of composites;

[000127] The composites can be filled into an expandable device to fill space to eliminate trial size implants in general;

[000128] The composites can be filled into any pressurized cavity that can be felled with bone cement and have a metal implant inserted, e.g., for bone stimulation;

[000129] Fracture fixation devices (hone plates, screws, pins on external fixators, etc.);

[00013©] Denial implants for bone healing;

[000131] Posterior instrumentation for spine fusion (pedicle screws, rods, etc); [O00132] Linkage to power a battery for a pacemaker;

[000133] Linkage to power any internal device/sensor;

[000134] Attachment to any load bearing part to stimulate internal organ/tissue healing;

[O00135] Lab on a chip devices that need power supplies;

[000136] Telemetry powering for sensing^■■■ "built in sensors";

[000137] Use in a continuous extrusion process for piezoelectric rods;

[000138} In combination with slight twisting/distortion/rotation of electrical field (or eould be mechanical) during extrusion as rods structures before curing to generate twist coupled sensors and actuators;

[O0013 J A variety of energy/power harvesting devices including:

|000140J Tires on any vehicle to power rechargeable batteries and provide vibrational damping;

[0001411 Drive shaft on a car to power rechargeable batteries;

[000142J Car paint c-r part of a car grill to power rechargeable batteries;

[O00143J "Rubber" surface on a floor to capture loads and convert to power; [000144] Application on load-bearing structures in vibration generating devices in a household to feed to power grid;

[000 45] Roads to capture vehicular loads;

[000146] More efficient wind mills - blades or other structures loaded to generate power;

[000147] Plates/structures in oceans/seas to capture wave loads;

[000141] Bleachers In sport stadiums to power novelty lights or feed power into the grid as a function of fan loading of bleachers;

[008149 ] Body of eel! phone to recharge batteries;

[SWISS] Structured components in building for energy harvesi/sensors/damping

[000151] Shingles on houses to translate wind forces and feed to power grid;

[000152] Bridge components for sensing/power generation;

6001331 ^&rts ^{m '} owe tools like jackharnmers or drills tor energy harvest sensors/damping;

[000154] Parts of construction equipment for energy harvest/sensors/damping;

[000155] Mechanical damping with piezoelectric structures;

[0001561 Use in structures in regions of high seismic activity to capture early detection and damping;

[©001571 Hook up to grid to form a giant network of sensors;

[0&015S] Snow ski vibration damping;

| 0IS j Self-heating boots;

1000160] Shoes with lighting;

|000161] Sensors for clothing;

[000162] Fabric made for various applications;

1000163] Sound proofing materials for damping;

[000164] Sails of sal! boats to generate ship power;

[000165] Incorporate with any power plant system to increase efficiency;

[000166] Poles in power lines;

f000!67] Piezoelectric transmission lines or conductive cables; [006I68J Road sensing lines/pads to trigger stop lights, sense presence of cars, etc;

0)016 ] Self-powered exoskeleton;

00170] ESeetiOrheologieal fluids;

[000I71J Fluid brakes and clutches in vehicles thai change viscosity based on applied pressure instead of electric field;

[000172] Heart blanket/sock for heart failure treatment (wrap around heart and contract based on applied voltage);

|000173] Treads on tanks;

[000174] Remote sensor with sustained power from loading vibration;

fOOOI 75J Front i¾wk on hike to power hike devices or provide vibration damping;

[0001 6| Total disc replacement. Endplates constructed of piezoelectric composite, with negative electrodes lining the interface between device and vertebrae, while the positive terminal is placed near the center of the device to ensure bone does not grow into, and impinge the dynamic parts. This should improve the bond between the device and vertebrae, while strengthening the vertebrae to avoid endplate subsidence, and ideally further securing the device so it does not migrate;

[000177] Use of composites in a positive (healing of tissue) or negative (stopping tissue growth) in any novel implant;

[000178] Reduction of biofouiing in implanted sensors through generation of svirface charges;

[000179] Air filters to kill bacteria/other pathogens through surface charges; and [000180] Self-sanitizing surface/structures,

[0001S1] F G. 4A shows an exemplary manufacturing set-up for use with dieSectrophoretic (DEP) formation of piezoelectric composites described herein. FIG. 4B shows an exemplary manufacturing set-tjp for use with piezoelectrophoretie (PEP) formation of piezoelectric composites described herein.

[0001821 The DEP manufacturing set-up 400 shown in FIG, 4A suitably comprises a moid apparatus 402 for holding shaped dispersion 206. Mold apparatus 402 suitably comprises an inlet 406 for introduction of dispersion 205 comprising the polymerizable matrix 202 material arid dispersed piezoelectric particles 204. The set-up further suitably comprises an electric field generator 412, connected to a first electrode 40S and second electrode 410, for application of an electric field to the shaped dispersion.

[000183] The PEP manufacturing set-up 414 shown in FIG. 4B_? is a modification of the DEP set-up 400. PEP set-up suitably further comprises insulating connectors 416 and 422, separating electrodes 408 and 410 from actuator 418 and load cell 424, respectively. Actuator 418 and load cell 424, are suitably a material testing system (MTS), e.g., an MTS 858 MiniBionix (MTS Systems Corporation, Eden Prairie, MM), comprising a plunger and load cell capable of applying a cyclic pressure 420 to the shaped dispersion 206. Inclusion of insulating connectors 416 and 422, allows for the application of an electric Field as well as the hydrostatic pressure, as described herein. Through computer or other external control, a cyclic pressure can he generated at the same frequency with an applied electric field. The electric fseld and the cyclic pressure can be applied in phase or out of phase with one another depending on the types of materials utilized.

Exa l 1; Preparation of 1-3 Composite ing DEP

[W0 84J Structured 1-3 composites were prepared using dielectrophoresis (DEP). The polymerizable matrix for these composites was a two part resin (3Q2-3M, Epotek), and the particles were 5 micrometer barium titanate. Composites were structured using an electric field strength of I KV/man and a frequency of 1 KHz,. The resulting dielectric and piezoelectric properties of the composite materials were characterized using well-known techniques as described below,

0SS185J Dielectric characterization was conducted using a Hioki 3522-50 LCR meter (Hioki EE Corporation, egano, Japan). This meter is used to assess the capacitance, and resistance of the samples, This information, coupled with knowledge of sample geometry, can be used to determine a sample's resistivity, conductivity, and dielectric constant. The meter cart also assess the dieleetric loss factor (tan3). Measurements are carried out at room temperature, at frequencies from DC to I KHz. Confidence intervals for each setup are constructed using a Student's T~test. Comparisons between control, DEP. and PEP structured materials at each volume traction are conducted using one-way ANOVA.

SCIiS6 Determination of piezoelectric properties are measured via direct or resonance methods. Resonance methods are widely used for piezoeeramie crystals, and are highly accurate in thai instance, However, when mechanical losses are high, which is likely in a quasi 1-3 composite, the quality of the results degrades. The direct method is easily implemented utilising a material testing system (MTS), and can readsiy provide accurate results for material use at low frequencies. Stress is applied to the sample, while simultaneously recording the charge generated by the sample. This is done by placing a capacitor in electrical parallel with the sample, and recording the voltage. Since capacitors follow the relation: Q ~ C*V, a plot of charge vs force cart be generated. The slope of this line represents the piezoelectric charge coefficient. The principal charge coefficient (drj, άη, and d¾j) is also measured. Electrodes are applied to samples in the 3 direction during manufacture, and as such, d$ ds_¾ and djj, can he readily measured, The piezoelectric voltage coefficients (g_y) can be calculated based on the d- coefficients, and dielectric constant of the material. This occurs as gy = d /ε. The piezoelectric properties provide information key to the material's use as both sensing and actuating elements. Confidence intervals for each setup are coiistiueted using a Student's T-test. Comparisons between control, DEP, and PEP structured materials at each volume fraction are conducted using one-way ANOVA.

00187] Results obtained compare well to the models presented for I~3 composites in Equations 3 and 4, below, as shown in FIG, 4. Piezoelectric charge cosffitissni for a 0-3 Piezoelectric charge c afficiefii fa? >¾ 1-3 composite composite - Die'eclrie cofssisfii of She matrix

%a - Dietecinc constant of tie 0-3 ¾~ Diaiectric constant of fse particles com os* R - Ratio of parties© size to ssstefpartiefe spacing is - Dseieciric co??sf¾eil of She Ψ - Particle volume fraction

pariieies Yt - cdufcs of elasticity of the mat™

- Frazoeisctne parisc!e cherge V_jj.- MocMas of elasticity of the particles in She constant poled direction

rs - Irwsrs© ctepcfa ssfiort factor d_Sj - Piezosiedric particte enarge constant Ψ - Particte miasm fraction

Example 2% Piezoelectric Com osite Spiral Fusi n Inte body Impl¾¾t |@i@i§S] Provided herein is the development of a piezoelectric composite biomaterial and interbody device (spinal implant) design for the generation of clinically relevant levels of electrical stimulation to help improve the rate of fusion for in patients.

[000189] A lumped parameter mode! of the piezoelectric composite implant was developed based on a model that has been utilized to successfully predict power generation for piezocer&mics. Seven variables (fiber material, matrix material, fiber volume fraction, fiber aspect ratio, implant cross-sectional area, implant thickness, and electrical load resistance) were parametrieally analyzed to determine their effects on power generation within implant constraints. Influences of implant geometry and fiber aspect ratio were independent of material parameters. For a cyciie force of constant magnitude, implant thickness was directly and cross-sectional area inversely proportional to power generation potential. Fiber aspect ratios above 30 yielded maximum power generation potential while volume fractious above 15 percent showed superior performance. These results demonstrate the feasibility of using composite piezoelectric biomaterials in medical implants, such as spinal implants, to generate therapeutic levels of direct current electrical stimulation.

Methods

Modes

[9δ 1 ©1 A mode! was developed to predict the power output of piezoelectric composites (16), The piezoelectric composite model was developed based on a similar model that has been utili ed to successfully predict power generation for piezoeeramics (17, IS). This circuit model can be broken down into four different sections: input voltage, equivalent mechanical elements, composite impedance, and load resistance (FIG, 6). The load resistance ( L) is the electrical resistance of the object to which the electrical power is being delivered.

€191] The circuit model was developed by constructing a lumped parameter model of the mechanical system, based on the mass, damping, and stiffness of the composite (FIG. 7).

This well-known model can be described by the second order differential equation presented in Equation 5.

F-M +B +Kx (Eq. 5)

F = external force

M ^~ effective mass - stiffness

x ~ mass di

- mass velocity

x = mass acceleration

0193J This model is coupled to ihe circuit model shown in FIG. 6 through the use of a piezoelectric, transformer ratio, (IS). When used, this ratio affects the mechanical performance described in Equation 5 by introducing an electrical damping term that effectively describes the amount of energy transferred from the mechanical to electrical system (19).

t = Thickness

A = Cross-sectional area

s ~ Composite compliance

©I 9 J When applied to the mechanical elements of the spring mass damper system, the transformer ratio establishes equivalent circuit elements which describe the conversion of mechanical vibrations to electrical energy (Equations 7-10).

5- 7) M (Eq. 8) K^')^→ (Eq. 9)

(Eq, 10)

[(MMH95| Furthermore, the composite Implant's electrical impedance can be determined by Equations 1 1 and 12. While piezoceramics are primarily capacitsve, piezoelectric composites also include a polymer matrix thai acts predominantly as a resistor at low frequencies. These were placed in parallel, representing the two parallel paths electricity has through the composite; through the capaciiive fibers or the resistive matrix. Combined, these elements represent the electrical impedance of the composite material.

Cp - ( 1 - 2-)™ (Eq. I ί)

[8®0i961 The equations presented above have been utilized and validated for low frequency homogeneous piezoceramic materials ( 18). Howe er, in order to utilize them to analyze piezoelectric composite materials, several composite material properties must first be defined. The composite's dielectric constant and piezoelectric charge coefficient have been theoretically and

14 for high aspect ratio

Eq. 13)

where s - Composite dielectric constant

Z] ~ Matrix dielectric constant

t2 Fiber dielectric constant

si - Matrix compliance

¾ ^:::: Fiber compliance

d™ Composite piezoelectric charge constat

dn - Fiber piezoelectric charge conslant

f™ Effective ratio of ihe electric field acting on the fiber

Ψ - Fiber volume fraction

|00D19?J The composite material's elastic modulus and electrical resistivity are based on equations for composites materials (Equations 15, 16). For these equations, 0-3 composite equations were used to approximate the quasi- 1-3 material, and produce a conservative estimate of electrical power generation

where

elastic modulus

Ej-Fiber elastic modulus

where

p i ^~ Matrix electrical resistivity

p 2 - Fiber electrical resistivity

Environmental Variables

[060198] The performance of a piezoelectric power generator depends on multiple variables, These variables relate not only to the material composition and implant geometry, but the environmental operating conditions as well. The environmental operating conditions, which include the applied force, frequency of compression, and electrical resistance of the surrounding tissue, have been reported by other investigators, and are discussed below (15, 21- 27).

1 The force on the implant is primarily controlled by the weight of the patient and the patient's activities. The majority of the patient's tipper body weight is supported by the spine. Furthermore, after a lumbar fusion, the majority of this weight is transferred directly through the fusion cage. During common activities such as walking, the force on the intervertebral disc in the lumbar region can range from 1 ,0 to 2.95 times body weight (21-24). However, with the inclusion of posterior instrumentation, the force on the implant itself is halved (25). For patients that have just undergone a spinal fusion and are recovering front surgery, walking is one of the most intense activities that can be expected. Since the average weight for an adult is reported to be 608 N (26), the average person would load an implant with between 300 and 900 N while walking. For this model, an intermediate value of 500 was utilized as the applied force.

] The frequency of implant compression also depends on the intensify of the activities performed by the patient. Most activities occur with frequencies less than 5 Hz. Walking, for example, usually occurs at a frequency between 1 ,2 and 2 Hz (23). It is possible to increase the frequency of implant stimulation by applying a high frequency, low amplitude stimulus to the patient, such as ultrasound; however, this would require additional patient compliance, and likely visits to the doctor or physical therapist. For this model, 1.2 Hz was used for the frequency of implant compression.

At the present time, FDA approved DC electrical stimulation devices are designed to deliver the appropriate current density to bone with an electrical impedance from 0 to 40 kO (ί 5). Experimentally, bone undergoing fracture healing has reported impedances between 4 and 7 kO (27). The load resistance that generates maximum power is determined in the subsequent analysis, and used to validate a stand-alone implant. Material and Implant Geometry Variables

|D0#202J n addition to the environment conditions, several of the variables affecting power generation cm be readily controlled during the manufacturing process, These include proper material selection and implant geometry. The materials issed in the composite suitably comprise a polymer matrix embedded with a dispersion of aligned piezoelectric fibers. The polymer matrix provides structural stability for the brittle, ceramic fibers, while the fibers provide the net piezoelectric properties to the composite.

[1)00203] For this study, two different materials are investigated for the piezoelectric fibers: PZT and BaTiGs (Table 1).

Table 1 : Material properties used in theoretical analysis.

[0ΘΘ2Θ4] PZT is one of the most commonly used piezoelectric materials due to its high piezoelectric properties and coupling coefficient (28). BaTiO¾ is considered a viable option due to its hiocompatibility and current use in irrspianiabie medical devices.

[000235J Several matrix materials are analyzed including epoxy, PEEK, PVDF, and PVDF-TrFE-CFE. PEEK is suitably utilized as it is commonly used in fusion cages due to its high strength, similar stiffness to bone, and excellent biocompatibility (29), A two-part epoxy (Epotek 302-3M) has been used previously in piezoelectric composite research. It was analyzed m the model to provide comparison to other composites (30). PVDF and PVDF-TrFE-CFE were analyzed due to their promising theoretical results with piezoelectric particle composites and biocornpatibility (16). The material properties used in the theoretical model are shown in Table L

[0θ@2{Μϋ] Additionally, implant geometry also affects the expected power generation. Cross-sectional area and thickness measurements were taken from commercially available small TLIF spinal fusion cages as well as large ALIF cages to provide a reasonable range of inputs for the theoretical model. Cross- sectional areas of these cages ranged from 120 to 325 mm^ and the thickness ranged from 5 to 20 mm. Typical ranges of fiber volume fraction (0-40%) and aspect ratios (1-1000) were also analyzed. Since tissue electrical properties are variable, the influence of load resistance was also studied by varying the circuit variable from 0-30 ΤΩ. Table 2 lists the ranges of these controllable variables thai were analysed to determine the influence of implant variables on power generation.

Table 2, Ranges of controllable variables for the composite when used as a spinal fusion cage.

Results

[$ 287] Seven variables from tbe model were studied to determine their influence on the electricity generated by the composite: fiber material, matrix material_s fiber volume fraction, fiber aspect ratio, implant cross-sectionai area, implant thickness, and load resistance.

[0 82§8] Preliminary tests established that for a cyclic force of constant magnitude, maximum power was generated with the largest implant thickness and the smallest cross-sectional area (FIGs, 8 and 9). These results were unaffected by changes in other variables, For the following analyses, the implant thickness was set to 20 mm and the cross-sectional area was set to 120 mm² in order to determine the potential maximum power output of this device.

[000209] The influence of fiber aspect ratio shows a large increase in power output (880%) from ratios off 1-30, followed by a smaller increase of 7.0% for ratios between 30-100, and almost no change (<1%) from 100-1000 (FIG. S O), Therefore, in order to generate maximum power, the fibers used in the composite suitably have an aspect ratio of at least 30. T hese trends result from drastic increases in material properties associated with high aspect ratio particles and correspond well with the experimental results of Van den Ende el ai. (12).

[000210] FIG. 11 illustrates the influence of fiber volume fraction and load resistance for an implant with a 120 mm² cross-sectional area, and thickness of 20 mm with fiber aspect ratio of 100. This implant size and shape can produce a peak power of 0,47 mW at a volume fraction of 31% and load resistance of 8.5 ΟΩ.

[010211 J The analysis performed above was conducted for all sets of matrix and fiber materials, it was found that the same trends were present, and thai peak performance was generated in each composite for the same specimen area, thickness, fiber aspect ratio, and fiber volume fraction. Therefore, using the implant geometry and fiber variables from the preceding analysis, the effects of using different materials were then compared by using the fiber and matrix variables given in Table 1 , The power generated was then plotted versus load resistance as shown in F G. 12, The FZT - PEEK composite generated a peak power of 2.1 aiW, compared to the BaTiOs - PEEK composite which generated 0.47 mW.

[0(10212] As the BaTi(¾ fibers were capable of producing an average rms power approximately 2.4 times the maximum power that is needed for clinical use and as BaTiOj materials are currently used in FDA approved implants, this fiber type was used to analyze the remaining matrix variables. The results for matrix materials showed no meaningful difference (<1 1%) in power generation between the highest and lowest output. Similar trends were seers for PZT fibers embedded in the various matrix materials.

Discussion

[09@213| According to this analysis, an implant comprising a 1-3 structured composite of BaTiO, fibers nd a PEEK matrix is suitably able to generate 2,4 times more power than the maximum currently used to stimulate bone growth, 0-3 composite equations were used to calculate the elastic modulus and electrical resistivity; however, the composites are actually quasi- 1-3 composites, The 1-3 composite equations are believed to overestimate the electrical outputs. Therefore the 0-3 composite equations provide a conservative estimate for these values, providing a minimum baseline for the material's electrical generation.

[§{M)214] A 31% fsber volume fraction yielded the largest peak power output for a 20 mm thick implant. Unlike spherical particles, for which theoretical models show a steadily increasing power output with volume fraction (16), the aligned fsber piezoelectric composite output does not exhibit a constantly increasing correlation to volume fraction and instead peaks at an intermediate value. This relationship is due to the variations in piezoelectric and dielectric constant created by the aligned Fibers of the 1-3 composite. At low volume fractions, the djj value increases rapidly with increasing volume fractions, but plateaus at a relatively low volume fraction, while the dielectric constant of the composite steadily increases with increasing volume fraction (12). The theoretical model demonstrates thai power generation increases with higher d33 values, but decreases with increasing fiber dielectric constant. Thus, the peak power output does not have a direct relationship with lber volume fraction.

[00021.5 Designing an implant that is thick with a small cross-sectional area is one way of increasing overall piezoelectric implant power output. Since the applied force magnitude remains constant, a smaller implant cross-sectional area results In increased implant stress, thus yielding higher power generation. However, the fusion cage must still be able to provide mechanical support for the spine while the vertebrae are fusing and not pose a risk for ersdplate subsidence. The grade of PEEK that is used in spinal implants has a fatigue strength of 60 MPa, and a compressive strength of 118 MPa, considerably larger than the 4.2 MPa stress level predicted in this theoretical analysis (31). A PEEK composite implant with typical geometry and a cross-sectional area of 120 mm³ is predicted to have a fatigue limit of 7.2 kN and should survive compressive loads up to 14,2 kK much larger than the anticipated in vivo loads,

[Θ0021β| Peak power for a monolithic piezoelectric composite occurs at a load resistance of 8,5 Gil, many orders of magnitude higher than the tissue resistance found in vivo (0-40 kil). A piezoelectric spinal fusion implant may require additional energy harvesting circuitry with a load resistance of S.5 GO and deliver the electricity generated to the desired fusion site. An alternative design utilizes multiple embedded electrodes to reduce the optimal load resistance. This method was proven to be effective for bulk piezoceramics, and is anticipated to work for composite materials as well (IS),

§0ft21?l The piezoelectric- implant parameters found to generate optimal power using a structured 1-3 BaTiQ_? fiber and PEEK matrix are summarized in Tabie 3.

^' able 3. Variables that generate maximum power for a BaTi03 - PEEK spinal fusion cage,

[ΘΘ02Ι8] A piezoelectric composite spina! implant with, these specifications suitably generates an average mis power of 0.33 mW_s which is 2,4 times greater than the target power of 0, 14 mW, A piezoelectric composite sptrsai fusion implant suitably delivers a higher current density than existing electrical stimulation devices, thereby speeding bone growth (14, 32). However, if a lower constant dose is required, the excess power generated during patient activity could be stored and distributed as needed when the patient is inactive, In addition, the generation of excess power means the piezoelectric composite implant could still effectively be utilized with cross- sectional areas up to 275 mm², or thicknesses as small as 9 mm, ali while still generating the target constant power of 0.14 mW.

Conclusion

[98H2!9f The piezoelectric spinal fusion cage analyzed in this study suitably increases success rates of spinal fusion, particularly in the difficult to fose patient population. This design fills a large unmet need in the medical community due to the low success rates of current spinal fusion methods in patients with compromised bone fusing ability. Unlike other bone growth stimulants, the piezoelectric spinal implant described herein would not add additional expense, instrumentation, or prolong the implantation procedure greatly, and is predominantly independent of patient compliance, A piezoelectric spinal implant would simply replace the interbody device currently used in the surgery and utilize the patient^'s own movement to help stimulate hone growth. Based on the model developed for piezoelectric composites, an implant made of BaTiOj and PEEK suitably generates sufficient power to improve the rate and quantity of bone growth, thereby increasing fusion success rates, thus reducing overall patient care costs.

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[900252J it will be readily apparent to one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the methods and applications described herein can he made without departing from the scope of any of the embodiments.

[δθ$253| It is to be understood that while certain embodiments have been illustrated and described herein, the claims are not to be limited to the specific forms or arrangement of parts described and shown, in the specification, there have been disclosed illustrative embodiments, and although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation. Modifications a d variations of the embodiments are possible in light of the above teachings. It is therefore to be understood that the embodiments may be practiced otherwise than as specifically described,

Claims

WHAT IS CLAIMED I&t

1. A method of making a spinal imp3ant_> the method comprising: a) preparing a thermosei, thermoplastic or thermoset thermopiasdc, or copolymer poi merizab!e matrix; b) dispersing a plurality of piezoelectric particles in the polymerizabSe matrix to generate a dispersion; c) shaping the dispersion; d) inducing an electric polarization in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particies form chains as a result of the induction of the electric polarization: and e) curing the dispersion to generate the spinal implant.

2. The method of claim 1 , wherein the shaping comprises injection, molding, extrusion, compression molding, blow molding or thermoforraingo

3. The method of claim 1, wherein the piezoelectric particies ejdiibit a Perovskite crystalline structure,

4. The method of claim 1, wherein the piezoelectric particles are selected from the group consisting of particies of barium titanaie, particles of hydr xyapatite, particies of apatite, particies of lithium sulfate momohydrate, pariseJes of sodium potassium niohate, particles of quartz, particles of lead zirconium titanate (PZT), particks of tartaric acid and po3y(vinylidene diiluoride) fibers.

5. The method of laim 1, wherein the inducing an electric polarization comprises applying an electric, field in a direction to the shaped dispersion.

6. The method of claim 1, wherein the inducing an electric polarization comprises applying a hydrostatic pressure to the shaped dispersion or changing the temperature of the shaped dispersion.

7. The method of claim 6, further comprising, prior to the curing in e), applying an electric field in a direction to the shaped dispersion.

S. The method of claim 5, wherein the applying an electric field comprises applying a field with a frequency of about 1 kHz to about 10 kHz and a field strength of about 1 Volt mm to about i fcV/mm,

9. The method of claim 7, wherein the applying an electric field comprises applying a field with a frequency of about 1 Hz to about 100 Hz and a field strength of about 1 Volt/mm to about 1 kV/rnm.

10. The method of claim 7, wherein the inducing in d) occurs before the applying an electric field.

1 1. The method of claim 7, wherein the inducing in d) occurs after the applying an electric field.

12. The method of claim 7_S wherein the inducing in d) and the applying an electric field occur simultaneously.

13. The method of claim \ 2, wherein the eiectric field is applied at the same frequency with a cyclic hydrostatic pressure.

14. The method of claim 1 , wherein the curing comprises cooling, UY curing, heat accelerated curing or compression curing the dispersion.

15. The method of claim 1, wherein the chains have a random orientation,

16. The method of ciaim 5, wherein at least about 10% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field,

17. The method of ciaim 16, wherein at least about 50% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field.

18. The method of claim 7, wherein at least ahout 10% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field.

19. The method of ciaim 18, wherein at least about 50% of the chains are aligned to within about ± 0 degrees of the direction of the applied eiectric field. 20, A spinal implant prepared by the method of claim 1.

21 , A spinal implant comprising a polymer matrix and a plurality of piezoelectric particles, wherein at least 40% of the piezoelectric particles are in the form of chains, and the composite is a 1-3 composite.

22, The sp nal implant of claim 1, wherein at least about 10% of the chains are aligned to within ±10 degrees of each other,

23, The spinal implant of claim 22, wherein at least about 50% of the chains are aligned to within ±10 degrees of each other,

24, The spinal implant of claim 21 , wherein the piezoelectric particles exhibit a Perovskite crystalline structure.

25, The spinal inrpiant of claim 21 , wherein the piezoelectric particles are selected from the group consisting of particles of barium titartaie, particles of hydroxyapatste_s particles of apatite, particles of lithium sulfate monohydrate, panicles of sodium potassium niobate, particles of quartz, particles of lead zirconium titanate (PZT), particles of tartaric acid and poly(vinylidene dsfiuonde) fibers,

26, The spina! implant of claim 21, wherein the implant generates a current density of between about 1 to about 250 microamps/crn² when compressed,

27, A method of making a piezoelectric composite, the method comprising: a) preparing a polymerizable matrix; b) dispersing a plurality of piezoelectric particles in the polymerizable matrix to generate a dispersion; c) shaping the dispersion: d) inducing an electric polarization in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particles form chains as a result of the induction of the electric polarization; and e) curing the dispersion.

2%, The method of claim 27, wherein the polymerizable matrix comprises:

L a thermoset polymer, copolymer and/or monomer;

IL a thermoplastic polymer, copolymer and/or monomer; or

111 a thertnosei ihermoplastic polymer or copolymer blend,

29. The method of claim 27, wherein the piezoelectric particles exhibit a Perovskite crystalline structure.

30. The method of claim 27, wherein the piezoelectric particles are selected from the group consisting of particles of barium titanate, panicles of - SO - hydroxyapatite, particles of apatite, particles of lithium sulfate monohydraie, particles of sodium potassium niohate, particles of quartz, particles of lead zirconium iiianate (ΨΖΎ), particles of tartaric acid and poiyiVrrsylidene difluofide) fibers.

31. The method of claim 27, wherein the shaping comprises injection molding, extrusion, compression molding, blow molding or thermoforming,

32. The method of claim 27, wherein the inducing an electric polarization comprises applying an electric field Irs a direction to the shaped dispersion.

33. The method of claim 27, wherein the inducing an electric polarization comprises applying a hydrostatic pressure to the shaped dispersion or changing the temperature of the shaped dispersion.

34. The method of claim 33. further comprising, prior to the curing in e), applying an electric field in a direction to the shaped dispersion.

35. The method of claim 32, wherein the applying an electric field comprises applying a field with a frequency of about 1 kHz to about 10 kHz and a field strength of about I Volt/mm to abont 1 kVolt rrsm.

36. The method of claim 34_; wherein the applying an electric field comprises applying a field with a frequency of about 1 Hz to about 100 GHz and a field strength of about 1 Volt/mm to about 1 kVo It/mm.

37. The method of cl im 34, wherein the inducing in d) occurs before t e applying an electric field.

3S. The method of claim 34, wherein the inducing in d) occurs after the applying an electric Held,

39. The method of claim 34, wherein the inducing in d) and the applying an electric field occur simultaneously,

40. The method of claim 39, wherein the electric field is applied at the same frequency with a cyclic hydrostatic pressure.

41. The method of claim 27, wherein the curing comprises cooling, UV curing, heat accelerated curing or compression curing the dispersion.

42. The method of claim 27, wherein the chains have a random orientation.

43. The method of claim 32, wherein at least about 10% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field.

44. The method claim 43, wherein at least about 50% of the chains are aligned to within about ±\ Q degrees of the direction of the applied electric field.

45. The method of M 34, wherein at least about 10% of the chains are aligned to within about ±10 degrees of the direction of the applied electric fseid.

46. The method claim 45, wherein at least about 50% of the chains are aligned to within about ±10 degrees of the direction of the applied electric field ,

47. A method of making a tissue-stimulating piezoelectric composite, the method comprising; a) preparing a ihennoset, thermoplastic or themoset/thermoplastic, or copolymer polymerizable matrix; b) dispersing a plurality of piezoelectric particles in the poiymerizable matrix to generate a dispersion; e) shaping the dispersion: d) inducing an electric polarization in the piezoelectric particles in the shaped dispersion, wherein at least 40% of the piezoelectric particles form chains as a result of the induction of the electric polarization; and e) curing the dispersion.

48. The method of claim 47, wherein the shaping comprises injection molding,, extrusion, compression molding, blow molding or thermo forming,

49. The method of claim 47, wherein the piezoelectric particles exhibit a Perovskite crystalline structure.

50. The method of claim 47, wherein the piezoelectric particles are selected from the group consisting of particles of barium iitanate, particles of hydroxyapatiie, particles of apatite, particles of lithium sulfate monohydrate, particles of sodium potassium niobate, particles of quartz, particles of lead zirconium titanate (PZT), particles of tartaric acid and poly{v½y|jderie difl oride) fibers.

5 L The method of claim 47, wherein the inducing an eleetric polarization comprises applying an electric field in a direction to the shaped dispersion,

52, The method of claim 47, wherein the inducing an electric polarization comprises applying a hydrostatic pressure to the shaped dispersion or changing the temperature of the shaped dispersion.

53. The method of claim 52, further comprising, prior to the curing in e), applying an electric field in a direction to the shaped dispersion.

54. The method of claim 51, wherein the applying an electric field comprises applying a field with a frequency of about 1 kHz to ahout 10 kHz and a field strength of ahout 1 Volt/mm to about 1 kV/mrn,

55. The method of claim 53, wherein the applying an electric field comprises applying a field with a frequency of about 1 Hz ΐο shout 100 Hz and a field strength of ahout 1 Volt/mm to about 1 kV/mm.

56. The method of cl im 53. wherein the inducing in d) occurs before the applying an electric field.

57. The method of claim 53, wherein the inducing in d) occurs after the applying an electric field.

58. The method of claim 53, wherein the inducing in d) and the applying an electric field occur simultaneously,

59. The method of claim 58, wherein the electric field is applied at the same frequency with a cyclic hydrostatic pressure.

60. The method of claim 47, wherein the curing comprises cooling, UV curing, heat accelerated curing or compression curing the dispersion.

61. The method of claim 47, wherein the chains have a random orientation.

62. The method of claim 51, wherein at least about 10% of the chains are aligned to within about ±10 degrees of the direction of die applied electric field.

63. The method of claim 62, wherein at least about 50% of the chains are aligned to within abont ±10 degrees of the direction of the applied electric field.

64. The method of claim 53, wherein at least about 10% of the chains are aligned to within abont ±10 degrees of the direction of the applied electric field,

65. The method of claim 64, wherein at least abont 50% of the chains are aligned to within abosit ±10 degrees of the direction of the applied electric field,

66. A piezoelectric composite prepared by the method of claim 27.

67. A tissue-stimulating piezoelectric composite prepared by the method of claim 47.

68. A piezoelectric composite comprising a polymer matrix and a plurality of piezoelectric particles, wherein at least 40% of the piezoelectric particles are in the form of chains and the composite has at least one dimension of 5 mm or greater.

69. The piezoelectric composite of claim 68, wherein the chains have a random orientation.

70. The piezoelectric composite of claim 68, wherein at least about 10% of the chains are aligned to within ±10 degrees of each other,

71. The piezoelectric composite of claim 70, wherein at least about 50% of the chains are aligned to within ±10 degrees of each other,

72. The piezoelectric composite of claim 68, wherein the composite is a 1 -3 composite.

73. The piezoelectric composite of claim 68, wherein the polymer is s thermoses polymer, a thermoplastic polymer or a themoset thermapl&stie polymer or copolymer blend.

74. The piezoelectric composite of claim 68, wherein the piezoelectric particles exhibit a Perovskite crystalline structure,

75. The piezoelectric composite of claim 68, wherein the piezoelectric particles are selected from the group consisting of particles of barium titarsate, particles of hydroxyapatite, particles of apatite, particles of lithium sulfate monohydrate, particles of sodium potassium niobate, particles of quartz, particles of lead zirconium tltanate (PZT), particles of tartaric acid and poiy{yinylidene difluoride) fibers,

76. The piezoelectric composite of claim 68, wherein the composite generates a current density of between ahoat 1 to ahout 250 microamps/errs² when compressed.

77. A tissue-stimulating piezoelectric composite comprising a polymer matrix and a plurality of piezoelectric particles, wherein at least 40% of the piezoelectric particles are in the form of chains, and the composite is a 1-3 composite.

78. The tissue-stimulating piezoelectric composite of claim 77, wherein at least about 10% of the chains are aligned to within ±10 degrees of each other.

79. The tissue-stimulating piezoelectric composite of claim 78, wherein at least about 50% of the chains are aligned to within ±10 degrees of each other.

80. The tissue-stimulating piezoelectric composite of claim 77, wherein the piezoelectric particles exhibit a Perovskite crystalline structure.

81. The tissue-stimulating piezoelectric composite of claim 77, wherein the piezoelectric particles are selected from the group consisting of particles of barium titanate, particles of hydroxyapatite, particles of apatite, particles of lithium sulfate nionohydrate, particles of sodium potassium niobatc, particles of quartz, particles of lead zirconium titanale (PZT), particles of tartaric acid and poSy(vinySidene dif!uoride) fibers.

82. The tissue-stimulating piezoelectric composite of claim 77, wherein the composite generates a current density' of between about 1 to about 250 microamps/cm² when compressed,