WO2005027735A2

WO2005027735A2 - Apparatus and method for enhancing bone formation

Info

Publication number: WO2005027735A2
Application number: PCT/US2004/030798
Authority: WO
Inventors: Hiroki Yokota; Shigeo Tanaka; Hui Bin Sun
Original assignee: Advanced Research And Technology Institute, Inc.
Priority date: 2003-09-19
Filing date: 2004-09-17
Publication date: 2005-03-31
Also published as: WO2005027735A3

Abstract

Apparatus and methods enhance bone formation. The methods and apparatus provide a mechanical load (60a, 60b) applied to the epiphysis (44, 45, 62) of a bone (24, 26, 64) associated with a joint (22). The magnitude of the mechanical load is oscillated and is applied periodically for a short durations of time. The applied mechanical force induces formation of trabecular (70) and cortical (68) bones. Embodiments of the apparatus include passively and actively actuated bands (28, 128, 228, 328) which are positioned around at least a portion of a joint and provide mechanical loading on the joint, for example, on the epiphysis of a bone and oriented traverse (54, 76) to the longitudinal axis (56, 78) of the bone.

Description

APPARATUS AND METHOD FOR ENHANCING BONE FORMATION

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60/504,532, filed September 19, 2003, the complete disclosure of which is expressly incorporated by reference herein.

FIELD OF THE INVENTION The present disclosure generally relates to apparatus and methods for enhancing bone formation, and more specifically, to apparatus and methods using mechanical loading to enhance bone formation.

BACKGROUND The consequences of loss of bone tissue include the functional hazards of a diminished and weakened skeletal structure which could result in fractures. Bone formation is stimulated by mobility and exposure to gravity; therefore, preventing bone loss is a health issue particularly to the aging and other populations having reduced mobility, as well as to astronauts residing outside of the earth's gravitational field. One method of enhancing bone formation is to use compressive mechanical loading applied along the longitudinal axis of a bone in order to create a strain in the bone. In particular, the mechanical load is applied to generate strain in the cortical bone of the diaphysis. Strain induced fluid flow is thought to produce osteogenic responses that result in enhanced bone formation. However, apparatus and methods preventing bone loss which include generating a strain in the diaphysis also offer drawbacks. For example, generating strain in the diaphysis in limb bones requires a loading device that is large enough to span the entire length of a long bone, for example, a femur or tibia. Accordingly, the portability and ease of use of such devices are detrimentally affected. In addition, it may be difficult to determine the appropriate loading magnitude for particular individuals; therefore, operation of such a device may cause unwanted bone fractures. Furthermore, enhancing bone formation by generating a strain in the diaphysis may require that all bones be treated independently. Moreover, the use of such devices can require dedicated exercise time which may not be easily incorporated into daily activities. In light of the above concerns, alternative strategies for enhancing bone formation are desirable.

SUMMARY A method and apparatus for enhancing the formation of, and/or strengthening of, bone, for example, humerus, ulna, radius, femur, tibia, and fibula, in accordance with the present disclosure, includes one or more of the following features or combinations thereof: The method of enhancing bone formation in a mammal can include applying a mechanical load to a joint of the mammal so that viscoelastic joint tissues of the joint are deformed. In one embodiment the method includes oscillating the amplitude of the mechanical load, for example at about 2 Hz, so that fluid flow is generated in the bones forming the joint. The fluid flow can be interstitial cellular fluid flow and include the diaphysis of a bone. The method can also include varying the amplitude of the mechanical load to generate a streaming potential measured on the periosteal surface of the diaphysis of the bones forming the joint, for example so that the peak-to-peak amplitude of the mechanical load is about 0.5 N. The joint can be, but is not limited to, one of the knee, ankle, hip, shoulder, elbow, and wrist, and the mechanical load in one embodiment is applied laterally to the joint to cause viscoelastic deformation of joint tissues. The method can also include applying a circumferential band around at least a portion of the joint and exercising the joint to vary the load applied to the joint by the band. The method can also include positioning a wall of a bladder in contact with the joint and advancing a fluid into the bladder. Alternatively, applying the mechanical load to the joint can include positioning a band around at least a portion of the joint and tightening the band. In another embodiment the method of enhancing bone formation in a mammal having a joint connecting a first bone and a second bone includes applying a mechanical load to the epiphysis of at least one of the first bone and the second bone. The magnitude of the mechanical load can be oscillated and the mechanical load can be applied laterally to the joint such that fluid flow is generated in at least one of the first bone and the second bone. The orientation of the mechanical load can be in a direction that is about transverse to the longitudinal axis of the bone and can be applied to the joint tissue connecting the first bone and the second bone. In yet another embodiment, the apparatus for enhancing bone formation includes a band configured to fit around at least a portion of a joint of a mammal, a bladder coupled to the band, and a pump in fluid communication with the bladder and operable to advance a fluid, for example water or air, into the bladder. The pump can have a controller for oscillating the volume of fluid in the bladder. The band can form a loop having an adjustable circumference. The band can also be a belt that defines a loop having a circumference configurable to fit around a joint and an electric motor operatively coupled to the belt and capable of varying the circumference of the loop. The band can alternatively include an electro-chemical material, for example, a polymer that undergoes dimensional changes upon exposure to an electric field, such as polypyrrole or polythiophene. Oscillation of the electric field can be used to change the circumference of the loop, thereby varying the mechanical load on the joint. In another exemplary embodiment, the apparatus for enhancing bone formation includes a band configured to be positioned around a joint and an element coupled to that band that is configured to apply lateral pressure to the joint. The band can include an elastic wrap. The element can also include a pad, for example a fluid filled bladder. In one embodiment two pads are positioned on opposite sides of the joint.

BRIEF DESCRIPTION FIGS. 1 A- ID are perspective views of joint loading devices according to the present invention, including: (A) manually driven device, (B) device having a fluid bladder driven by an electric pump, (C) a device having a tension band driven by an electric motor, and (D) device having an artificial muscle actuated by an electric field generator; FIG 2 is a schematic diagram of mechanical loading along the longitudinal axis of a bone and the predicted resulting fluid flow; FIG. 3 A is a schematic illustration of lateral mechanical loading of the epiphysis of a bone and the predicted resulting fluid flow according to the present invention; FIG. 3B is a coronal section view of a joint including the joint loading device of FIG. 1A positioned around the joint; FIG. 4A is a block diagram of a piezoelectric mechanical loader used in one disclosed study; FIG. 4B is a perspective view of the piezoelectric mechanical loader of FIG. 4A; FIG. 5A is an elevational view of lateral mechanical loading of a murine elbow according to one disclosed study; FIG. 5B is a schematic diagram of mechanical loading along the longitudinal axis of a mouse ulnae according to one disclosed study; FIGS. 6A-6C graphically illustrates calcein stained murine ulnae cross sections resulting from one disclosed study, including: (A) a control ulnae (no loading) having very faint staining, (B) a loaded ulnae having strong staining, and (C) magnified periosteal bone within the boxed region of (B) showing newly formed bone between two calcein injections; FIGS. 7A-7C graphically illustrate histomo hometric parameters representing the effects of murine elbow lateral loading for one disclosed study, including: (A) mineralizing surface, (B) mineral apposition rate, and (C) bone formation rate; FIGS. 8A-8C graphically illustrate the mechanical loading force and streaming potentials according to one disclosed study, including: (A) loading force, (B) streaming potential resulting from longitudinal loading of murine ulnae, and (C) streaming potentional resulting from lateral loading of murine elbow; FIGS. 9A-9C graphically illustrate histomorphometric parameters measured at various displacements from the site of the loading of control and experimental murine bone according to one disclosed study, including: (A) mineralizing surface, (B) mineral apposition rate, and (C) bone formation rate; FIG. 10 graphically illustrates streaming potentials induced by longitudinal loading (bending) of murine and lateral loading of murine elbow joints according to one disclosed study; FIG. 11 A and 1 IB graphically illustrate the phase shift angle and dissipation energy versus frequency of viscoelastic parameters in response to sinusoidal loading of murine joints according to one disclosed study; FIG. 12 is a time sequence of photographs illustrating the change in fluorescent intensity of lacunae in the midshaft of a murine femur prior to photo bleaching and subsequent recovery due to molecular transport; and FIG. 13 A and 13B graphically illustrate the change in fluorescent intensity of the lacunae of FIG. 12, including: (A) intensity change, (B) logrithmic ratios of the intensity.

DETAILED DESCRIPTION While the disclosure is susceptible to various modifications and alternative forms, a specific embodiment thereof has been shown by way of example and will herein be described in detail. It should be understood, however, that there is no intent to limit the disclosure to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims. The present invention provides apparatuses and methods for enhancing bone formation. Refering to FIG. 3 A, the methods and apparatuses provide mechanical loads 60a and 60b that are applied to epiphysis 62 of bone 64 associated with a joint, for example, joint 22 shown in FIG. 3B. The magnitude of mechanical force 62a and 62b is oscillated and is applied periodically for short durations of time, for example, for a few minutes per day. Applied mechanical loads 60a and 60b induce formation of trabecular and cortical bone tissue. Referring to FIGS. 1A-1D, exemplary embodiments 20, 120, 220, and 320 of the apparatus include passively (20) and actively (120, 220 and 320) actuated bands 28, 128, 228, and 328 which are positioned around at least a portion of joint 22 to provide mechanical loading on the joint. For example, referring to FIG. 3B, in one exemplary embodiment, mechanical loads 60a and 60b are applied on epiphysis 44 at 45 of bone 46 and 48, respectively, and are oriented about traverse 54 to longitudinal axis 56 of bones 46 and 48. The magnitude of mechanical force 60a and 60b may be oscillated and applied periodically for short durations of time, for example, for a few minutes. Applied mechanical loads 60a and 60b induce and enhance formation of trabecular and cortical bone of proximal bone 24 and distal bone 26. Referring to FIG. 2, prior known method 80 of enhancing bone formation in bone 82 includes using surfaces 84a and 84b to apply compressive mechanical loads 86a and 86b along longitudinal axis 88 of bone 82. Mechanical loads 86a and 86b provides strain throughout hard cortical bone 90, including in diaphysis 92 of bone 82. Because of the curvature (not shown) along the diaphysis of some bones 82, the strain induced by mechanical loads 86a and 86b may also provide bending along diaphysis 92. The strain induced by mechanical load 86a and 86b induces fluid flow 94 substantially throughout bone 82, including in cortical bone 90 of diaphysis 92. In contrast, referring to FIG. 3 A, exemplary method 58 of the present invention enhances bone formation by inducing fluid flow 74, including in cortical bone 68 of diaphysis 64, by applying compressive mechanical loads 60a and 60b to induce strain in only epiphysis 62, not in diaphysis 66. One of the advantages of exemplary method 58 over prior method 80 is that epiphysis 62 of bone 64 includes outer cortical bone 68 and inner cancellous bone 70 that is more elastic than the bone structure along diaphysis 66. Exemplary method 58 provides the desired fluid flow 74 at a lower magnitude of mechanical loading than for prior method 80. The arrangement of surfaces 61a and 61b and orientation of mechanical loads 60a and 60b and the resulting strain in bone 64 therefore reduces the overall dimensions of a mechanism supporting surfaces 61a and 61b and reduces the likelihood of the induced strain fracturing hard cortical bone 68 of diaphysis 66. It is believed that the fluid flow enhancing bone formation is interstitial fluid flow that enhances proliferation and differentiation of osteoblasts and osteocytes, thereby providing the osteogenic response. Although exemplary method 58 of enhancing bone formation provides a pair of surfaces 61a and 61b along traverse axis 76, alternate configurations can be provided. For example, one surface 61a can be utilized to apply a mechanical load 60a against another portion of epiphysis 62 so long as desired fluid flow 74 and a reduced level strain in cortical bone 68 of diaphysis 66 (over prior method 80) are achieved. Fluid flow 74 can be approximately determined, for example, by measuring the streaming potential (voltage induced by a coupling between ion flux and fluid movement) on periosteal surface 67 of diaphysis 66. Exemplary method 68 may be useful for enhancing the formation of bone in the human anatomy, particularly long bones such as those associated with limbs and joints, for example, those associated with the knee, ankle, hip, shoulder, elbow, and wrist. Exemplary experimental studies disclosed herein utilized various embodiments of exemplary piezoelectric mechanical loader 400 shown in FIGS. 4A and 4B to demonstrate enhancement of bone formation according to the present invention in mammals, specifically in murine bone. Referring to FIGS. 5A and 5B, specifically, bone formation in ulnae 404a was studied using lateral mechanical loading 406 (FIG. 5A) applied to elbow joint 408 using screw 412 and loading element 414 of loader 400. Additionally, the studies of bone formation in ulnae 404a subject to lateral mechanical loading 406 were compared to ulnae 404b subject to conventional longitudinal mechanical loading 410. The detailed methods and findings of the exemplary experimental studies are disclosed below. Referring again to FIG. 1 A, an exemplary embodiment of the present invention includes passively-driven apparatus 20. Apparatus 20 is sized and structured to be positioned over joint 22 of limb 23, for example a knee joint of a patient. Apparatus 20 can be used for applying a mechanical load(s) to one or both of proximal bone 24 and distal bone 26 of limb 23. Apparatus 20 includes band 28 which is sized and shaped to span at least a portion of knee 22. In the exemplary embodiment, band 28 is sized to fully circumscribe joint 22 and can be a continuous band of material or may include attachment 30 for coupling together opposite ends of band 28 or for adjusting the circumference of band 28. Band 28 can include, for example, a flexible material having elastic properties, for example similar to those used in known flexible joint supports. Band 28 can also include a semi-rigid or rigid material, such as those used in joint guards for sports. Exemplary apparatus 20 is passively driven in that after band 28 is positioned over at least a portion of joint 22, flexing or otherwise exercising joint 22 transmits mechanical loads from apparatus 20 to one or both of bones 24 and 26. For example, after snuggly securing apparatus 20 around the circumference of limb 23 at joint 22, bending limb 23 at joint 22 expands and contracts the diameter of limb 23, generating and transmitting a varying mechanical load into joint 22 from the varying tension of apparatus 20 against limb 23. Additionally, to enhance the mechamcal load generated on joint 22 by apparatus 20, loading element 32, for example a bladder, may be coupled to band 28. For example, loading element 32 can be a rigid or semi rigid pad or a flexible fluid filled bladder for transmitting a mechanical load to joint 22. Specifically, apparatus 20 may include manually-operated fluid pump 36, for example an air pump, coupled to loading element 32 by hose 38. Pump 36 can be used to deliver air through hose 38 and into loading element 32, thereby increasing the thickness of loading element 32 and increasing the magnitude of the mechanical load. Referring to FIG. 3B, a coronal section view of limb 23, including joint 22, proximal bone 24, and distal bone 26, it is shown having exemplary apparatus 20 approximately centered on joint 22. Apparatus 20 includes loading elements 32 that are located on opposite sides of joint 22 and have walls 40 in loading contact with the portion of limb 23 surrounding joint 22. Loading elements 32 may be coupled to band 28. Band 28 can merely position loading elements 32 in place relative to limb 23, or, band 28 can be tensioned against loading elements 32, thereby providing mechanical loads 60a and 60b through joint tissue 42 to epiphysis 44 and 45 of bones 46 and 48, respectively. Alternatively, loading elements 32 can be positioned or structured to apply mechanical loads 60a and 60b to primarily only one of epiphysis 44 and 46. Loading elements 32, as discussed above, can also include bladders for varying the magnitude of mechanical load 60a and 60b. The position and structure of loading elements 32 of exemplary apparatus 20 are designed to provide mechanical loads 60a and 60b along transverse axis 54. Traverse axis 54 is about perpendicular to longitudinal axis 56 of bones 24 and 26. If an alternative loading vector for mechanical loads 60a and 60b is desired, loading elements 32 and band 28 can be positioned and/or structured differently to provide the desired loading orientation, for example, to provide a greater load on one of bones 24 and 26. One exemplary method of the present invention uses exemplary apparatus 20 to provide brief periods of periodic mechanical loads 60a and 60b, for example for three minutes per day. Additionally, mechanical loads 60a and 60b may be oscillated in magnitude, for example sinusoidally between 2 Hz and 30 Hz with a peak to peak load sufficient to induce bone formation enhancing interstitial fluid flow, for example, about 100 N; however, other load magnitudes and other waveforms and frequencies can be utilized. Alternatively exemplary embodiments of apparatus 20 may include only one or more than two loading elements 32, a loading element that extends around a substantial portion of the circumference of limb 23, or other configurations conducive to transmitting mechanical loads to epiphysis 44 and 46. Other bone formation enhancing treatment modalities requiring steady or oscillating applications of a mechanical loads can also be performed using exemplary apparatus 20. Exemplary apparatuses 120, 220, and 320 shown in FIGS. IB-ID include some of the features of exemplary apparatus 20 and also include electrical powered actuators 136, 236, and 336 for controlling the mechanical loads produced by apparatuses 120, 220, and 320. Referring to FIG. IB, exemplary apparatus 120 includes band 128, bladder(s) 132, and electric powered fluid pump 136. Band 28 can be constructed as disclosed for band 128 of exemplary apparatus 20. Bladders 132 provide mechanical loading to joint 22 of limb 23 as disclosed above; however, the magnitude of the mechanical load can be actively controlled by the fluid flow provide by electric fluid pump 136. Specifically, pump 136 pumps fluid, for example air or water, through hoses 138 into bladders 132. In one exemplary embodiment, bladders 132 are located on opposite sides of joint 22 so that as the volume of fluid contained in bladders 32 increase, the tension of band 128 forces bladders 132 against limb 23, thereby increasing the mechanical loading on joint 22. The magnitude of the mechanical loading can be decreased by using pump 136 to remove fluid from bladders 132, or by a switching device such as a valve which controls fluid flow out of bladder 132 under the force applied from the tension of band 128. Exemplary apparatus 120 may also include a manual or automatic control (not shown) for pump 136 to provide one of the above-mentioned treatment modalities, for example periodically providing an oscillating mechanical load to joint 22 in order to enhance bone formation. Referring to FIGS. 1C and ID, exemplary embodiments 220 and 320 include bands 228 and 328, respectively, which form a belt like structure having an adjustable tension for providing a mechanical loading on joint 22 of limb 23. Specifically, exemplary apparatus 220 includes mechanical actuator 236, for example an electric motor, that is operatively coupled to band 228 by tensioning device 237. For example, tensioning device 237 can be a rotating shaft coupled to a portion of band 228 such that rotation of the device 237 spools a portion of band 228 onto or off of device 237, thereby adjusting the tension and therefore the mechanical load transmitted to joint 22 of limb 23. Control of actuator 236 therefore provides control of the magnitude and oscillation frequency of the mechanical load to joint 22. Referring to FIG. ID, exemplary embodiment 320 similarly includes band 328 having an adjustable tension; however, band 328 is constructed from a material having electrical chemical properties that facilitate dimensional changes to the material upon application of an electric signal. For example, band 328 can be constructed from an artificial muscle material, for example, a polymer, such as polypyrrole or polythiophene, that undergoes dimensional changes upon exposure to an electric field. Exemplary apparatus 320 includes electric field generator 336 for varying the tension of band 328 on limb 323, thereby varying the mechanical load provided to joint 22. For example, an electric signal for driving electric field generator 36 has an amplitude proportional to the magnitude of the desired mechanical load and a frequency equal to the desired mechanical load oscillation frequency. Biomechanical parameters such as air pressure generated in the bladder

32, 132 and the torque applied to the band 228, 328 around joint 22 can be chosen so that fluid flow would be induced in bone without disturbing any function or structure of joint 22. For apparatus 20, 122 that may be driven by air pressure approximately 40 kPa (5.8 psi) was needed to provide 0.5 N to murine elbows in the second exemplary study discussed below. Assuming that 100 N is used to press a lateral wall of a human knee joint, 51 kPa (7.4 psi) is required for a 50 mm in diameter bladder 32, 132. For instance, pump 136 may be a micro air pump driven at 6-24 NDC with 180 g weight (available from Sensidyne, of Clearwater, FL). For apparatus 220, 320 driven by tensioning the circumferential band 228, 328, FIGS. 1 C and ID, the tensile stress in the band, σ_t, is: σ_t = Pr/t where P = pressure, r = radius of a supporter, and t = thickness of a band. WithP = 51 kPa, r = 50 mm, and t = 3 mm, σ_t is estimated as 0.85 MPa. Since the required force to induce σ , is σ_twt with w = width of a band 228, (50 mm), motor 236 with 5-mm torque arm needs to generate about 0.64 Νm. For example, a gear motor (3363020, available from Igarashi Motors, of St. Charles, IL) having dimensions of 20 mm x 24.5 mm x 29 mm (110 g) can generate up to 1.0 Νm at 12 V. Electrochemical materials such as a polypyrrole polymer and a polythiophene polymer can be used as an artificial-muscle-like actuator 328 for apparatus 320. These polymers can be stretched or compressed through conformational changes inducible in an electrical field. Actuators can be formed in any shape, for example, belts, and it can easily generate strain of 10 % and stress above 20 MPa with a small amount of electricity. For example, a conductive polypyrrole polymer (available from EAMEX Co., of Osaka, Japan) with a cross- sectional area of 50 mm (width) x 3 mm (thickness) can generate 189 Ν (Hara, S, Zama T, S S, Takashima W, Kaneto K. 2003. Highly stretchable and powerful polyprrole linear actuators. Chemistry Letters, 32:576-577.). A first exemplary experimental study compared bone formation in murine ulnae exposed to mechanical loading with bone formation in nonloaded control murine ulnae. Twenty female C57BL/6 mice (14 weeks old) with a body weight of approximately 20 g were used for the study. Each mouse was mask- anesthetized using 2% isoflurane. The mechanical loading was applied with piezoelectric loader 400 (FIGS. 4A and 4B) to right arm 402a (See, Tanaka, S.M., Alam, I.M. and Turner, CH. (2003) Stochastic resonance in osteogenic response to mechanical loading. FASEB J, 17, 313-314.) for 3 minutes per day for three consecutive days to elbow 408 through a lateral medial direction as shown in FIG. 5 A. Left arms were used as nonloaded control specimens. Loading force 416 was sinusoidal at 2 Hz with a peak-to-peak force of 0.5 N, as shown in FIG. 8A. In order to avoid local stress concentrations between joint 408 and loading element 414, the surface of loading element 414 was covered with a silicon rubber sheet (not shown). The exemplary mechanical loader 400 used for the study includes an electro-mechanical loading structure and instrumentation. Specifically, structure 430 supports loading element 414 and cantilever 446, coupled to structure 430, supports loading screw 412. Loading screw 412 has an adjustable displacement relative to loading element 414. Specimen 402 to be loaded is positioned between screw 412 and element 414 and screw 412 is adjusted to contact specimen 402. Data acquisition board/command generator 436 provides a command signal to piezo driver 434, which in turn drive piezoelectric actuator 432. Actuator 432 is mechanically coupled to loading element 414 and provides the desired mechanical load commanded by command generator 436. Instrumentation of mechanical loader 400 includes strain gauge 444 mechanically coupled to cantilever 446 and electrically coupled to strain gauge conditioner 438 and data acquisition board 436. Strain gauge 444 provides monitoring and control of the mechanical load applied to the specimen. Displacement sensor 448 is coupled to cantilever 446 and measure the variation in displacement relative to lever 450 coupled to loading element 414. Switch 442 selectively electrically couples data acquisition board 436 to signal conditioner 440 which is electrically coupled to displacement sensor 448. Switch 442 also selectively electrically couples data acquisition board 436 to electrode 452. Electrode 452 is placed in contact with specimen 402 for measuring the electrical potential of specimen 402 relative to the ground of loader 400. All mice were, given an injection of 0.05 ml saline containing 1% calcein 2 and 6 days after the last application of mechanical load, and ulnae 404a/b were harvested 13 days after the loading. Harvested ulnae 404a/b were fixed in 10% formalin for 2 days. After dehydration by immersion in a series of efhanol solutions, ulnae 404a/b were embedded in methyl methacrylate. Transverse sections 405a/b (FIGS. 6A-6C) 50 um in thickness were cut at 2.5 mm distal from elbow 408 using a diamond wire saw, and ground with sand paper (#400) to about 20 um in thickness. The sections were examined with a fluorescence microscope. Using a semiautomatic digitizing system (Bioquant available from R&M Biometrics, of Nashville, TN), three morphometric parameters were determined for the periosteal surface of ulnae 404a/b, including mineralizing surface (MS/BS, %), mineral apposition rate (MAR, um/day), and bone formation rate (BFR/BS, um³/um²/year), where MS = sum of the length of the double-labeled perimeter and half of the single-labeled perimeter, BS = total length of the perimeter, MAR = average radial distance 418 (FIG. 6C) between the two labels per day, and BFR = MS/BS x MAR x 3.65 (Hsieh, Y.F. and Turner, CH. (2001) Effects of loading frequency on mechanically induced bone formation. Journal of Bone and Mineral Research, 16: 918-924). Streaming potentials were measured as a voltage generated between electrode 452 on a periosteal surface of an ulnar midshaft and a common ground for loading system 400. The periosteal surface connected to the electrode was dissected free of muscle and was always kept moist with a saline solution. A 16-bit data- acquisition board operated by a computer was used to record streaming potentials at a 250-usec interval. In order to examine statistical significance in the histomorphometric data, ANOVA analysis (using Statview, Version 5.0, available from SAS Institute Inc., of Cary, NC) was conducted with a significance level at p < 0.05. Bone histomorphometry with fluorescent cacein-labeling revealed that elbow loading significantly stimulated bone formation. Cross section 405a (FIGS. 6B and 6C) of ulna diaphysis 2.5 mm distal (16% of ulnar length) to elbow 408, clearly showed double labeling 418 on a periosteal surface with a sinusoidal loading for 3 minutes per day for 3 days on the elbow, as compared with cross section 405b of unloaded control ulna. Three bone morphometric parameters, MS/BS (mineralizing surface, p=0.0002), MAR (mineral apposition rate, p=0.045), and BFR/MS (bone formation rate, p=0.012), were significantly increased by elbow loading , as shown in FIGS. 7A-7C. The increase in MS/BS, MAR, and BFR/MS was 3.2-fold, 3.0-fold, and 7.9-fold, respectively. Streaming potential, induced by a coupling between ion flux and fluid movement, is a good indicator of strain-induced fluid flow in bone (Beck, B.R., Qin, Y.X., McLeod, K.J., and Otter, M.W. (2002) On the relationship between streaming potential and strain in an in vivo bone preparation. Calcif Tissue Int, 71, 335-343). In response to joint loading at 2 Hz with 0.5-N force, harmonic potentials were observed that were synchronized with the mechanical stimuli, as shown in FIGS. 8A-8C Longitudinal axis loading to ulna 404b, shown in FIG. 5B, one of the conventional bone loading methods to induce strain in cortical bone and bone formation (Tanaka et al., 2003; Robling, A.G. and Turner, CH. (2002) Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone, 31, 562-569), also generated a streaming potential with a magnitude on the same order as lateral joint loading (FIG. 5 A). The histomorphometric data demonstrates that lateral joint loading requires a lower magnitude of loading force (0.5 N peak-to-peak) to induce bone formation than the conventional axial bone loading methods which requires over 1 N peak-to-peak force (Robling et al., 2002). Conventionally a joint has been considered as a shock absorber that protects bone from impact loading (Voloshin, A., Wosk J., Brull M. 1981. Force wave transmission through the human locomotor system. J Biomech Eng, 103:48- 50). In the first exemplary study, however, joint loading showed a significant increase in bone formation on a periosteal surface of diaphysis cortical bone. It has been well-recognized that the osteogenic responses can be induced by bone strain in vivo (Rubin, C.T. and Lanyon, L. E. (1985) Regulation of bone mass by mechanical strain magnitude. Calcified Tissue International, 37:411-417; Turner, C. H., Forwood, M. R, Rho, J. Y., and Yoshikawa, T. (1994) Mechanical loading thresholds for lamellar and woven bone formation. Journal of Bone and Mineral Research, 9:87-97) and fluid flow in vitro (You, J., Yellowly, C. E., Donahue, H. J., Zhang, Y., Chen, Q., and Jacobs, C. R. (2000) Substrate deformation levels associated with routine physical activity are less stimulatory to bone cells relative to loading-induced oscillatory fluid flow. Journal of Biomedical Engineering, 122:387-393). Since streaming potential is an indicator of fluid flow in bone, the data on streaming potentials and bone morphometry demonstrate that joint loading can induce fluid flow and stimulate bone formation without causing strain in cortical bone. In a second exemplary experimental study of bone formation in mechanically loaded murine ulnae, twenty C57BL/6 mice (female, 14 weeks old) with a body weight of approximately 20 g were used and the mice were anesthetized as in the first study. In order to examine the effects of loading to joints (joint pushing), lateral mechanical loading 406 (FIG. 5A) was applied to murine elbow 408 in a lateral-medial direction in a similar fashion to the first exemplary study and also mechanical loading 410 (FIG. 5B) was applied along the longitudinal axis of murine ulnae 404b. An injection of 0.05 ml saline containing 1% calcein was given to mice 2 and 6 days after the last application of mechanical loading and ulnae 404a were harvested and preserved as for the first exemplary study. Using a diamond wire saw, transverse sections 50 um in thickness were cut at 1.0 mm, 2.5 mm, and 4.5 mm distal from an elbow, and ground to approximately 20 um in thickness. Using the Bioquant semiautomatic digitizing system, three morphometric parameters, shown in FIGS. 9A- 9C, mineralizing surface (MS/BS, %), mineral apposition rate (MAR, um/day), and bone formation rate (BFR/BS, um³/um²/year), were determined on a periosteal surface, where MS = sum of the length of double-labeled perimeter and half of single- labeled perimeter, and BS = total length of perimeter, MAR = average radial distance between the two labels per day, and BFR = MS/BS x MAR x 3.65 (Hsieh, Y. F. and Turner, C H. (2001) Effects of loading frequency on mechanically induced bone formation. Journal of Bone and Mineral Research, 16:918-924). Symbols 'a' and 'b' in FIGS. 9A-9C indicate statistical significance atp < 0.05 and p < 0.01, respectively. Streaming potentials were measured as for the first exemplary study, and are shown in FIG. 10 for lateral joint loading 406 (FIG. 5 A), loading along the longitudinal axis (ulna bending) 410 (FIG. 5B), and no loading. The linear regression lines are y=36.5x+0.22 (r²=9.73) for ulna bending, and y=24.5x+1.77 (r²=91.46) for joint loading. To determine the effects of joints on the frequency responses of two viscoeleastic parameters, phase shift angle and dissipation energy shown in FIGS. 11 A and 1 IB, axial mechanical loading (ulna bending) 410 shown in FIG. 5B, was performed on ulnae 404b with intact joints (solid line) as well as ulnae 404b lacking both elbow and hand joints (dashed line). Frequencies were in the range at 2 to 30 Hz. Phase shift angle, an indicator of viscosity, was determined as a phase difference between the measured displacement and the applied force using a Fourier analysis. Dissipation energy per unit time, uJ/s, was determined numerically by integrating an area inside a hysteresis loop in the force-displacement relationship. In order to examine statistical significance in the histomorphometric data, ANONA analysis (using StatView) was conducted with a significance level at p < 0.05. The histomorphometric analysis of cortical bones at the three different distal locations along ulnae 404a revealed a significant increase in three bone parameters, mineralizing surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR/BS) as shown in FIGS. 9A-9C Regardless of the distal distance from loaded elbow 408, joint loading 406 for 3 min per day for 3 consecutive days elevated an amount and a rate of newly formed bone compared to the control ulnae. Referring again to FIG. 10, the results clearly show that both ulna bending 410 and elbow pushing (joint loading) 406 induced streaming potentials in response to sinusoidal loads at approximately 0.1 Ν force. The slope for the ulna bending was 1.5-fold higher than that for the joint pushing, suggesting that the ulna bending involved with two joints is a stronger inducer of fluid flow than the joint loading for a single elbow joint. The higher slope for the ulna bending, however, does not imply that the ulna bending is more efficient to induce bone formation than the joint pushing. In the ulna bending, the force required to induce a statistically significant amount of new bone is about 2.3 Ν (Robling and Turner, 2002) M. In the joint pushing, the same amount of new bone is formed with about 0.5 Ν force. In a conventional view, bone formation is stimulated by fluid flow induced by deformation of cortical bone. This strain-induced fluid flow is considered to trigger the osteogenic responses of osteoblasts and osteocytes. Based on the new bone formation and the induction of streaming potentials by the joint loading in the first and second exemplary studies, a novel biomechanical mechanism for fluid flow is proposed. Although there is no intent to be limited by any particular mechanism, the inventive mechanism, for example, apparatuses 20, 120, 220 and 320 (FIGS. 1A- 1D) provide load-induced fluid flow in cortical bone that is mainly generated through deformation of viscoelastic joint tissues. A pair of joints capping a cortical bone act as a source and a sink of fluid flow, and deformation of rigid cortical bone is not required to induce fluid flow. In using apparatuses 20, 120, 220, and 320, a frequency of mechanical loads- in the Hz range should be chosen. An efficiency of any energy transfer from the apparatus to bone is affected by the viscoelastic parameters of joint tissues and bone. Using ulnae with and without intact joints, two mechanical parameters (phase shift angle and dissipation energy per second) were determined in response to sinusoidal mechanical loads at 2 - 30 Hz, as shown in FIGS. 11 A and 1 IB. The ulnae with intact joints (solid line, including hand and elbow joints) showed a local maximum of the phase shift angle and dissipation energy at 17 Hz, while the ulnae without intact joints (dashed line) did not show any peak in these parameters. The results suggest that a murine elbow can dissipate energy most effectively at approximately 17 Hz and oscillatory loads at this frequency with the supporter may maximally stimulate bone formation. A third exemplary experimental study examined fluid flow associated with mechanical loading of a bone. Mechanical loads can stimulate bone formation, and load-driven fluid flow is considered to enhance proliferation and differentiation of osteoblasts and osteocytes. Fluid flow has been visualized indirectly ex vivo and in vivo through a histological analysis (Knothe Tate M et al (2000) J. Exp. Biol. 203 2737-2745.), and a fluorescence recovery after photo-bleaching (FRAP) technique was used to detect real-time molecular transport in lacunae (Wang L et al (2003) 50™ Arm. Meeting ORS 327.). Histomorphometric studies completed by the inventors suggest that the mechanical loads applied to the epiphysis underneath the joint enhance formation of trabecular and cortical bones (Tanaka SM et al (2004) Biol. Sci. Space 18 41-44). In order to evaluate any alteration in molecular transport with this joint-loading modality, a mechanical loader (not shown) similar to loader 400 was constructed that could be used with a confocal microscopy for the FRAP procedure. The loader was capable of applying force up to ~1 N at any loading frequency, and the apparent time constant of molecular transport was determined with and without the mechanical loading. The results suggest that molecular transport is enhanced with the joint-loading modality. For the third study, the femurs of C57BL/6 mouse (female, 15 weeks old) with a body weight of ~ 20 g were used. The mouse was mask-anesthetized using 2% isoflurane. Uranine (fluorescein sodium salt, C20H1 ()O5Na2, 376 Da) was injected into the tail vein, and the femur was isolated 30 min after injection. A Zeiss LSM 510 Meta confocal microscope equipped with a femtosecond pulse laser system (available from Spectra-Physics of Mountain View, CA) for multi-photon imaging was used. The excitation wavelength was at 800 nm. The fluorescence signal was collected by either an internal detector with a fully opened pinhole or by a non-descanned detector. The emission filter was 505-550 nm band pass. The images were acquired on a Zeiss Axioplan-2 upright microscope with a 20X air plan-apochromat, NA 0.75 objective. The FRAP images, for example, those shown in FIG. 12, were collected using the time series function in the LSM 510 program. Each image has a frame size of 512 X 512 pixels, and a pixel length is 0.3 um in each dimension. The images were collected using a relatively low laser power, whereas a higher laser power was used for photo-bleaching a predefined region containing a single lacuna. At least one image was collected prior to photo-bleaching, and subsequent images after photo-bleaching was acquired at a 3- to 10-second interval. The mechanical loader was mounted on the microscope to evaluate the effects of molecular transport with and without the joint-loading modality. The piezoelectric actuator (LPD12060X, available from Megacera of Japan) was driven by a piezo driver (PZD700 M/S, available from Trek of Medina, NY), and controlled by a BNC-2110 interface (National Instruments of Austin, TX) and a custom-made MatLab program. The mechanical loads were applied to the epiphysis of the femur underneath the knee. The sinusoidal loads were ~ 0.5 N at 2 Hz for 3 min. A cluster of lacunae stained with uranine were captured in cortical bone approximately 8 mm apart from the loading site, and the zoomed image with a canalicular network around the lacuna was obtained. A series of images (FIG. 12) before and after photo-bleaching shows a temporal recovery of fluorescent signals in the lacuna. In order to estimate the apparent diffusion coefficient, the intensity ratio was defined, where c = fluorescent intensity as a function of time, tP^re = time zero prior to photo-bleaching, tP^0St = time zero after photo-bleaching, and λ = apparent diffusion coefficient, as shown in FIGS 13 A and 13B. The temporal change of fluorescent intensity was modeled using an exponential function in a form of {1 - exp(-t/τ)}, where τ was defined as an apparent time constant for the recovery after photo-bleaching. The value of r was estimated as 19.4±9.3 sec (control; N = 17) and 10.7±6.4 sec (joint-loading; N = 10), suggesting that the transport of uranine was stimulated in cortical bone by the loads applied to the femoral epiphysis. FIG. 13 A illustrates the intensity change of fluorescent intensity after photo-bleaching and FIG. 13B illustrates logarithmic ratios of the intensity change defined as y(t). The slope is proportional to λ , i.e., the apparent diffusion coefficient. The observed enhancement of molecular transport is consistent with load-driven bone formation (Tanaka SM et al (2004) Biol. Sci. Space 18 41-44). The FRAP results suggest that with the joint-loading modality fluid flow in cortical bone can be generated without deformation of cortical bone itself. While the disclosure has been illustrated and described in detail in the foregoing description, such illustration and description is to be considered as exemplary and not restrictive in character, it being understood that only the preferred embodiments have been shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected.

Claims

CLAIMS:

1. A method (58) of enhancing bone formation in a mammal, comprising applying a mechamcal load (60a, 60b) to a joint (22) of the mammal so that viscoelastic joint tissues (42, 44, 45) of the joint are deformed.

2. The method of claim 1 , further comprising oscillating the magnitude of the mechamcal load so that fluid flow (72, 74) is generated in the bones (24, 26, 64) forming the joint.

3. The method of claim 2, wherein the fluid flow includes the diaphysis (44, 48, 66) of a bone.

4. The method of claim 2, wherein the fluid flow includes interstitial cellular fluid flow.

5. The method of claim 1 , further comprising varying the magnitude of the mechanical load to generate a streaming potential measured on the periosteal surface (67) of the diaphysis of the bones forming the joint.

6. The method of claim 1 , wherein the magnitude of the mechamcal load is oscillated at about 2 Hz.

7. The method of claim 1 , wherein the peak-to-peak magnitude of the mechanical load is about 100 N.

8. The method of claim 1 , wherein the j oint is one of the knee, ankle, hip, shoulder, elbow, and wrist, and the mechanical load is applied laterally to the joint to cause viscoelastic deformation of joint tissues.

9. The method of claim 1 , wherein the mechanical load is applied to the epiphysis of at least one bone of the joint.

10. The method of claim 1, comprising applying a circumferential band (28, 128, 228, 328) around at least a portion of the joint.

11. The method of claim 10, wherein applying a mechanical load to a joint includes exercising the joint to vary the load applied to the joint by the band.

12. The method of claim 1, further comprising positioning a wall (40) of a bladder (32) in contact with the joint, and wherein applying the mechanical load to the joint includes advancing a fluid into the bladder.

13. The method of claim 1 , further comprising positioning a band around at least a portion of the joint, and wherein applying the mechanical load to the joint includes tightening the band.

14. A method (58) of enhancing bone formation in a mammal having a joint (22) connecting a first bone (24) and a second bone (26), the method comprising applying a mechanical load (60a, 60b) to the epiphysis (44, 45) of at least one of the first bone and the second bone.

15. The method of claim 14, further comprising oscillating the magnitude of the mechanical load.

16. The method of claim 14, wherein the j oint is one of the knee, ankle, hip, shoulder, elbow, and wrist, and the mechanical load is applied laterally (54, 76) to the joint such that fluid flow (72,74) is generated in at least one of the first bone and the second bone.

17. The method of claim 14, further comprising positioning a wall

(40) of a bladder (32) in contact with the joint, and wherein applying the mechanical load to the joint includes advancing a fluid into the bladder.

18. The method of claim 14, further comprising positioning a band (28, 128, 228, 328) around at least a portion of the joint, and wherein applying the mechanical load to the j oint includes tightening the band.

19. A method (58) of enhancing bone formation in a mammal, the method comprising applying a mechamcal force (60a, 60b) to the epiphysis (44, 45, 62) of a bone of the mammal, the mechanical force oriented in a direction that is about transverse (54, 76) to the longitudinal axis (56, 78) of the bone.

20. The method of claim 19, further comprising oscillating the magnitude of the mechanical force.

21. A method of enhancing bone formation in a mammal having (i) a first bone (24) and a second bone (26), (ii) a joint (22) between the first bone and the second bone, and (iii) joint tissue (42) onnecting the first bone and the second bone, the method comprising: placing a surface (40) in lateral contact with the joint; and urging the surface against the joint such that a mechamcal force (60a, 60b) is applied to the joint tissue.

22. The method of claim 21, further comprising moving the surface to oscillate the magnitude of the mechanical force.

23. An apparatus (20, 120) for enhancing bone formation, comprising: a band (28, 128) configured to fit around at least a portion of a joint (22) of a mammal; a bladder (32) coupled to said band; and a pump (36, 136) in fluid communication with the said bladder, wherein said pump is operable to advance a fluid into the bladder.

24. The apparatus of claim 23, wherein said fluid is at least one of a liquid and a gas.

25. The apparatus of claim 23, wherein said band forms a loop having an adjustable circumference.

26. The apparatus of claim 23, further comprising a controller for controlling said pump to oscillate the volume of fluid in the bladder.

27. An apparatus (220, 320) for enhancing bone formation, comprising: a belt (228, 328) that defines a loop, said loop having a circumference configurable to fit around a joint (22) of a mammal; and an electric motor (236) operatively coupled to said belt, wherein actuation of said electric motor varies the circumference of said loop.

28. The apparatus of claim 27, further comprising a controller for controlling said electric motor to oscillate the circumference of said loop.

29. An apparatus (320) for enhancing bone formation, comprising: a band (328) that (i) defines a loop having a circumference configured to fit around a joint (22) of a mammal and (ii) includes an electro-chemical material; and an electrical signal operatively coupled to said electro-chemical material, and wherein said electrical signal causes the circumference of said loop to vary.

30. The apparatus of claim 29, wherein the electro-chemical material is a polymer that undergoes dimensional changes upon exposure to an electric field.

31. The apparatus of claim 29, wherein the electro-chemical is at least one of polypyrrole polymer and polythiophene polymer.

32. The apparatus of claim 29, further comprising an electric field generator (336), and wherein said electrical signal is coupled to the electro-chemical by an electric field generally by said electric field generator.

33. The apparatus of claim 32 wherein the strength of said electric field oscillates, thereby varying the circumference of the loop.

34. The apparatus of claim 29, wherein said band is configured to apply pressure to the epiphysis (44, 45) of a bone (24, 26) associated with the joint.

35. An apparatus (20, 120, 220, 320) for enhancing bone foπnation, comprising: a band (28, 128, 228, 328) configured to be positioned around a joint; and an element (32, 132) coupled to said band and configured to apply lateral pressure to the joint.

36. The apparatus of claim 35, wherein said band includes an elastic wrap.

37. The apparatus of claim 35, wherein said element includes a pad.

38. The apparatus of claim 37, wherein said pad includes a fluid filled bladder.

39. The apparatus of claim 35, wherein said element include two pads positionable on opposite sides of the joint.

40. The apparatus of claim 35, further comprising an actuator (36, 136, 236, 336) coupled to at least one of said band and said element, said actuator configured to vary said lateral pressure.

41. A method of strengthening bone, comprising: positioning a circumferential belt (28, 128, 228, 328) around a joint (22) located between a first bone (24) and a second bone (26) of a mammal; and tensioning the belt to apply a load (60a, 60b) to the joint, the load inducing fluid flow in at least one of the first bone and the second bone.

42. The method of claim 41 , wherein the tension of the belt is oscillated.