Abstract
A bone implantable medical device made from a biocompatible material, preferably comprising titania or zirconia, has at least a portion of its surface modified to facilitate improved integration with bone. The implantable device may incorporate a surface infused with osteoinductive agent and/or may incorporate holes loaded with a therapeutic agent. The infused surface and/or the holes may be patterned to determine the distribution of and amount of osteoinductive agent and/or therapeutic agent incorporated. The rate of release or elation profile of the therapeutic agent may be controlled. Methods for producing such a bone implantable medical device are also disclosed and employ the use of accelerated Neutral Beam irradiation, wherein the Neutral Beam is derived from an accelerated gas cluster ion beam irradiation for improving bone integration.
Claims
1. A method of modifying a surface of a bone-implantable medical device comprising the steps of: coating at least a first portion of the surface of the medical device with an osteoinductive agent to form a coated surface region, said at least a first portion of the surface comprising a metal, an oxide, a ceramic or combinations thereof; and during a first irradiating step, irradiating at least a portion of the coated surface region with a first accelerated and focused Neutral Beam, derived from a gas cluster ion beam, from which ions have been removed and consisting essentially of neutral gas monomers, wherein the first irradiating step forms a shallow surface and subsurface layer less than or equal to 10 nanometers and comprising embedded molecules and/or dissociation products of the osteoinductive agent.
2. The method of claim 1, wherein the shallow surface and subsurface layer is an infused surface layer.
3. The method of claim 1, wherein the osteoinductive agent comprises, separately or in combination, any of the materials from the group consisting of: a nutrient material, tricalcium phosphate, hydroxyapatite, Bioglass 45S5, Bioglass 58S, a bone growth-stimulating agent, a growth factor, a cytokine, a TGF- protein, a BMP, a GPI-anchored signaling protein, an RGM, and a growth regulatory protein.
4. The method of claim 1, wherein the surface comprises titanium, titania, or zirconia.
5. The method of claim 1, further comprising the steps, prior to the coating step: forming a gas cluster ion beam; and during a second irradiating step, irradiating at least a second portion of the surface of the medical device with the gas cluster ion beam to clean the at least a second portion of the surface.
6. The method of claim 1, further comprising the steps, prior to the coating step: forming a second accelerated Neutral Beam; and during a second irradiating step, irradiating at least a second portion of the surface of the medical device with the second accelerated Neutral beam to clean the at least a second portion of the surface.
7. The method of claim 1, wherein the first irradiating step further comprises employing a mask to control the at least a portion of the coated surface region that is irradiated.
8. The method of claim 1, wherein the first irradiating step further comprises positioning the medical device with respect to the first accelerated Neutral Beam to control the at least a portion of the coated surface region that is irradiated.
9. The method of claim 1, further comprising the steps of: forming one or more holes in the surface of the medical device; loading at least one of the one or more holes with a therapeutic agent; and during a third irradiating step, irradiating an exposed surface of the therapeutic agent in at least one loaded hole with a third accelerated and focused Neutral Beam consisting essentially of neutral monomers and derived from a gas cluster ion beam, from which ions have been removed, to form a barrier layer at the exposed surface.
10. The method of claim 9, wherein the third accelerated Neutral Beam is derived from an accelerated gas cluster ion beam.
11. The method of claim 9, wherein the barrier layer controls an elution rate of therapeutic agent.
12. The method of claim 9, wherein the barrier layer controls a rate of inward diffusion of a fluid into the hole.
13. A method of modifying a surface of a bone-implantable medical device comprising the steps of: forming one or more holes in the surface of the medical device; first loading at least one of the one or more holes with a first therapeutic agent; and during a first irradiating step, irradiating an exposed surface of the first therapeutic agent in at least one loaded hole with a first accelerated and focused Neutral Beam, derived from a gas cluster ion beam, and consisting essentially of neutral monomers, to form a first barrier layer at the exposed surface in the at least one loaded hole.
14. The method of claim 13, wherein the one or more holes are disposed on the surface in a predetermined pattern to distribute the first therapeutic agent on the surface according to a predetermined distribution plan.
15. The method of claim 13, wherein at least one of the one or more holes is loaded with a second therapeutic agent different from the first therapeutic agent.
16. The method of claim 14, wherein at least one of the one or more holes is loaded with a first quantity of the first therapeutic agent that differs from a second quantity of the first therapeutic agent loaded in at least another of the one or more holes.
17. The method of claim 13, wherein the first loading step does not completely fill the at least one hole, and following the first irradiating step further comprising the steps of: second loading the at least one incompletely filled hole with a second therapeutic agent overlying the first barrier layer; and during a second irradiating step, irradiating an exposed surface of the second therapeutic agent in at least one second loaded hole with a second accelerated and focused Neutral Beam, derived from a gas cluster ion beam, and consisting essentially of neutral monomers, to form a second barrier layer at the exposed surface in the at least one loaded hole.
18. The method of claim 17, wherein the first barrier layer and the second barrier layer have different properties for controlling elution rate of the first and second therapeutic agents.
19. The method of claim 17, wherein the first accelerated Neutral Beam is derived from a first gas cluster ion beam and further wherein the second accelerated Neutral Beam is derived from a second gas cluster ion beam.
20. A method of modifying a surface of a bone-implantable medical device comprising the steps of: coating at least a first portion of the surface of the medical device with an osteoinductive agent to form a coated surface region; and during a first irradiating step, irradiating at least a portion of the coated surface region with a first accelerated and focused Neutral Beam derived from a gas cluster ion beam and consisting essentially of neutral gas monomers to form a barrier layer from a top surface of the osteoinductive agent to control elution of the osteoinductive agent.
21. A method of modifying a surface of a bone-implantable medical device comprising the steps of: forming one or more holes in the surface of the medical device; first loading at least one of the one or more holes with a first therapeutic agent; and during a first irradiating step, irradiating an exposed surface of the first therapeutic agent in at least one loaded hole with a first accelerated and focused Neutral Beam, derived from a gas cluster ion beam and consisting essentially of neutral gas monomers, to form a first barrier layer at the exposed surface in the at least one loaded hole.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0063] For a better understanding of the present invention, together with other and further objects thereof reference is made to the accompanying drawings, wherein:
[0064] FIG. 1 is a schematic illustrating elements of a GCIB processing apparatus 1100 for processing a workpiece using a GCIB;
[0065] FIG. 2 is a schematic illustrating elements of another GCIB processing apparatus 1200 for workpiece processing using a GCIB, wherein scanning of the ion beam and manipulation of the workpiece is employed;
[0066] FIG. 3 is a schematic of a Neutral Beam processing apparatus 1300 according to an embodiment of the invention, which uses electrostatic deflection plates to separate the charged and uncharged beams;
[0067] FIG. 4 is a schematic of a Neutral Beam processing apparatus 1400 according to an embodiment of the invention, using a thermal sensor for Neutral Beam measurement;
[0068] FIGS. 5A and 5B show comparison of a drug coating on a cobalt-chrome coupon representing a drug eluting medical device, wherein processing with a Neutral Beam produces a superior result to processing with a full GCIB;
[0069] FIG. 6 is a view of a prior art bone-implantable medical device, a dental implant device;
[0070] FIG. 7 A is a view of a dental implant device with holes for loading an osteoinductive agent or other medicine as may be employed in embodiments of the invention;
[0071] FIG. 7B is a view of a dental implant device with selected portions of its surface coated with an osteoinductive agent according to an embodiment of the invention;
[0072] FIG. 7C shows an ion beam irradiation step in the formation of a GCIB infused layer in portions of the surface of a dental implant device according to an embodiment of the invention;
[0073] FIG. 7D shows a view of a dental implant device having a surface with an infused osteoinductive agent according to an embodiment of the invention;
[0074] FIG. 7E shows a view of a dental implant device with an infused osteoinductive agent on a portion thereof, further having holes that are loaded with a medicine and/or an osteoinductive agent according to an embodiment of the invention;
[0075] FIG. 7F shows a GCIB irradiation step in the formation of a thin barrier layer in the surface of therapeutic agent loaded in holes in a dental implant device according to an embodiment of the invention;
[0076] FIGS. 8A, 8B, 8C, and 8D show detail of the steps for loading a hole in a bone-implantable medical device with a therapeutic agent, and forming a thin barrier layer thereon using ion beam irradiation according to embodiments of the invention;
[0077] FIG. 9 shows a bone-implantable hip joint prosthesis employing embodiments of the invention; and
[0078] FIG. 10 shows a cross sectional view of the surface of a bone-implantable medical device having a variety of therapeutic agent-loaded holes according to the invention and pointing out the diversity and flexibility of the invention.
DETAILED DESCRIPTION OF THE DRAWINGS
[0079] In the following description, for simplification, item numbers from earlier-described figures may appear in subsequently-described figures without discussion. Likewise, items discussed in relation to earlier figures may appear in subsequent figures without item numbers or additional description. In such cases items with like numbers are like items and have the previously-described features and functions, and illustration of items without item numbers shown in the present figure refer to like items having the same functions as the like items illustrated in earlier-discussed numbered figures.
[0080] In an embodiment of the invention, a Neutral Beam derived from an accelerated gas cluster ion beam is employed to process insulating (and other sensitive) surfaces.
[0081] Reference is now made to FIG. 1, which shows a schematic configuration for a GCIB processing apparatus 1100. A low-pressure vessel 1102 has three fluidly connected chambers: a nozzle chamber 1104, an ionization/acceleration chamber 1106, and a processing chamber 1108. The three chambers are evacuated by vacuum pumps 1146a, 1146b, and 1146c, respectively. A pressurized condensable source gas 1112 (for example argon) stored in a gas storage cylinder 1111 flows through a gas metering valve 1113 and a feed tube 1114 into a stagnation chamber 1116. Pressure (typically a few atmospheres) in the stagnation chamber 1116 results in ejection of gas into the substantially lower pressure vacuum through a nozzle 1110, resulting in formation of a supersonic gas jet 1118. Cooling, resulting from the expansion in the jet, causes a portion of the gas jet 1118 to condense into clusters, each consisting of from several to several thousand weakly bound atoms or molecules. A gas skimmer aperture 1120 is employed to control flow of gas into the downstream chambers by partially separating gas molecules that have not condensed into a cluster jet from the cluster jet. Excessive pressure in the downstream chambers can be detrimental by interfering with the transport of gas cluster ions and by interfering with management of the high voltages that may be employed for beam formation and transport. Suitable condensable source gases 1112 include, but are not limited to argon and other condensable noble gases, nitrogen, carbon dioxide, oxygen, and many other gases and/or gas mixtures. After formation of the gas clusters in the supersonic gas jet 1118, at least a portion of the gas clusters are ionized in an ionizer 1122 that is typically an electron impact ionizer that produces electrons by thermal emission from one or more incandescent filaments 1124 (or from other suitable electron sources) and accelerates and directs the electrons, enabling them to collide with gas clusters in the gas jet 1118. Electron impacts with gas clusters eject electrons from some portion of the gas clusters, causing those clusters to become positively ionized. Some clusters may have more than one electron ejected and may become multiply ionized. Control of the number of electrons and their energies after acceleration typically influences the number of ionizations that may occur and the ratio between multiple and single ionizations of the gas clusters. A suppressor electrode 1142, and grounded electrode 1144 extract the cluster ions from the ionizer exit aperture 1126, accelerate them to a desired energy (typically with acceleration potentials of from several hundred V to several tens of kV), and focuses them to form a GCIB 1128. The region that the GCIB 1128 traverses between the ionizer exit aperture 126 and the suppressor electrode 1142 is referred to as the extraction region. The axis (determined at the nozzle 1110), of the supersonic gas jet 1118 containing gas clusters is substantially the same as the axis 1154 of the GCIB 1128. Filament power supply 1136 provides filament voltage V.sub.f to heat the ionizer filament 1124. Anode power supply 1134 provides anode voltage V.sub.A to accelerate thermoelectrons emitted from filament 1124 to cause the thermoelectrons to irradiate the cluster-containing gas jet 1118 to produce cluster ions. A suppression power supply 1138 supplies suppression voltage V.sub.S (on the order of several hundred to a few thousand volts) to bias suppressor electrode 1142. Accelerator power supply 1140 supplies acceleration voltage V.sub.Acc to bias the ionizer 1122 with respect to suppressor electrode 1142 and grounded electrode 1144 so as to result in a total GCIB acceleration potential equal to V.sub.Acc. Suppressor electrode 1142 serves to extract ions from the ionizer exit aperture 1126 of ionizer 1122 and to prevent undesired electrons from entering the ionizer 1122 from downstream, and to form a focused GCIB 1128.
[0082] A workpiece 1160, which may (for example) be a medical device, a semiconductor material, an optical element, or other workpiece to be processed by GCIB processing, is held on a workpiece holder 1162, which disposes the workpiece in the path of the GCIB 1128. The workpiece holder is attached to but electrically insulated from the processing chamber 1108 by an electrical insulator 1164. Thus, GCIB 1128 striking the workpiece 1160 and the workpiece holder 1162 flows through an electrical lead 1168 to a dose processor 1170. A beam gate 1172 controls transmission of the GCIB 1128 along axis 1154 to the workpiece 1160. The beam gate 1172 typically has an open state and a closed state that is controlled by a linkage 1174 that may be (for example) electrical, mechanical, or electromechanical. Dose processor 1170 controls the open/closed state of the beam gate 1172 to manage the GCIB dose received by the workpiece 1160 and the workpiece holder 1162. In operation, the dose processor 1170 opens the beam gate 1172 to initiate GCIB irradiation of the workpiece 1160. Dose processor 1170 typically integrates GCIB electrical current arriving at the workpiece 1160 and workpiece holder 1162 to calculate an accumulated GCIB irradiation dose. At a predetermined dose, the dose processor 1170 closes the beam gate 1172, terminating processing when the predetermined dose has been achieved.
[0083] FIG. 2 shows a schematic illustrating elements of another GCIB processing apparatus 1200 for workpiece processing using a GCIB, wherein scanning of the ion beam and manipulation of the workpiece is employed. A workpiece 1160 to be processed by the GCIB processing apparatus 1200 is held on a workpiece holder 1202, disposed in the path of the GCIB 1128. In order to accomplish uniform processing of the workpiece 1160, the workpiece holder 1202 is designed to manipulate workpiece 1160, as may be required for uniform processing.
[0084] Any workpiece surfaces that are non-planar, for example, spherical or cup-like, rounded, irregular, or other un-flat configuration, may be oriented within a range of angles with respect to the beam incidence to obtain optimal GCIB processing of the workpiece surfaces. The workpiece holder 1202 can be folly articulated for orienting all non-planar surfaces to be processed in suitable alignment with the GCIB 1128 to provide processing optimization and uniformity. More specifically, when the workpiece 1160 being processed is non-planar, the workpiece holder 1202 may be rotated in a rotary motion 1210 and articulated in articulation motion 1212 by an articulation/rotation mechanism 1204. The articulation/rotation mechanism 1204 may permit 360 degrees of device rotation about longitudinal axis 1206 (which is coaxial with the axis 1154 of the GCIB 1128) and sufficient articulation about an axis 1208 perpendicular to axis 1206 to maintain the workpiece surface to within a desired range of beam incidence.
[0085] Under certain conditions, depending upon the size of the workpiece 1160, a scanning system may be desirable to produce uniform irradiation of a large workpiece. Although often not necessary for GCIB processing, two pairs of orthogonally oriented electrostatic scan plates 1130 and 1132 may be utilized to produce a raster or other scanning pattern over an extended processing area. When such beam scanning is performed, a scan generator 1156 provides X-axis scanning signal voltages to the pair of scan plates 1132 through lead pair 1159 and Y-axis scanning signal voltages to the pair of scan plates 1130 through lead pair 1158. The scanning signal voltages are commonly triangular waves of different frequencies that cause the GCIB 1128 to be converted into a scanned GCIB 1148, which scans the entire surface of the workpiece 1160. A scanned beam-defining aperture 1214 defines a scanned area. The scanned beam-defining aperture 1214 is electrically conductive and is electrically connected to the low-pressure vessel 1102 wall and supported by support member 1220. The workpiece holder 1202 is electrically connected via a flexible electrical lead 1222 to a faraday cup 1216 that surrounds the workpiece 1160 and the workpiece holder 1202 and collects all the current passing through the defining aperture 1214. The workpiece holder 1202 is electrically isolated from the articulation/rotation mechanism 1204 and the faraday cup 1216 is electrically isolated from and mounted to the low-pressure vessel 1102 by insulators 1218. Accordingly, all current from the scanned GCIB 1148, which passes through the scanned beam-defining aperture 1214 is collected in the faraday cup 1216 and flows through electrical lead 1224 to the dose processor 1170. In operation, the dose processor 1170 opens the beam gate 1172 to initiate GCIB irradiation of the workpiece 1160. The dose processor 1170 typically integrates GCIB electrical current arriving at the workpiece 1160 and workpiece holder 1202 and faraday cup 1216 to calculate an accumulated GCIB irradiation dose per unit area. At a predetermined dose, the dose processor 1170 closes the beam gate 1172, terminating processing when the predetermined dose has been achieved. During the accumulation of the predetermined dose, the workpiece 1160 may be manipulated by the articulation/rotation mechanism 1204 to ensure processing of all desired surfaces.
[0086] FIG. 3 is a schematic of a Neutral Beam processing apparatus 1300 of an exemplary type that may be employed for Neutral Beam processing according to embodiments of the invention. It uses electrostatic deflection plates to separate the charged and uncharged portions of a GCIB. A beamline chamber 1107 encloses the ionizer and accelerator regions and the workpiece processing regions. The beamline chamber 1107 has high conductance and so the pressure is substantially uniform throughout. A vacuum pump 1146b evacuates the beamline chamber 1107. Gas flows into the beamline chamber 1107 in the form of clustered and unclustered gas transported by the gas jet 1118 and in the form of additional unclustered gas that leaks through the gas skimmer aperture 1120. A pressure sensor 1330 transmits pressure data from the beam line chamber 1107 through an electrical cable 1332 to a pressure sensor controller 1334, which measures and displays pressure in the beamline chamber 1107. The pressure in the beamline chamber 1107 depends on the balance of gas flow into the beamline chamber 1107 and the pumping speed of the vacuum pump 1146b. By selection of the diameter of the gas skimmer aperture 1120, the flow of source gas 1112 through the nozzle 1110, and the pumping speed of the vacuum pump 1146b, the pressure in the beamline chamber 1107 equilibrates at a pressure. P.sub.B, determined by design and by nozzle flow. The beam flight path from grounded electrode 1144 to workpiece holder 162, is for example, 100 cm. By design and adjustment P.sub.B may be approximately 610.sup.5 torr (810.sup.3 pascal). Thus the product of pressure and beam path length is approximately 610.sup.3 torr-cm (0.8 pascal-cm) and the gas target thickness for the beam is approximately 1.9410.sup.14 gas molecules per cm.sup.2, which is observed to be effective for dissociating the gas cluster ions in the GCIB 1128. V.sub.Acc may be for example 30 kV and the GCIB 1128 is accelerated by that potential. A pair of deflection plates (1302 and 1304) is disposed about the axis 1154 of the GCIB 1128. A deflector power supply 1306 provides a positive deflection voltage V.sub.D to deflection plate 1302 via electrical lead 1308. Deflection plate 1304 is connected to electrical ground by electrical lead 1312 and through current sensor/display 1310. Deflector power supply 1306 is manually controllable. V.sub.D may be adjusted from zero to a voltage sufficient to completely deflect the ionized portion 1316 of the GCIB 1128 onto the deflection plate 1304 (for example a few thousand volts). When the ionized portion 1316 of the GCIB 1128 is deflected onto the deflection plate 1304, the resulting current, I.sub.D flows through electrical lead 1312 and current sensor/display 1310 for indication. When V.sub.D is zero, the GCIB 1128 is undeflected and travels to the workpiece 1160 and the workpiece holder 1162. The GCIB beam current I.sub.B is collected on the workpiece 1160 and the workpiece holder 1162 and flows through electrical lead 1168 and current sensor/display 1320 to electrical ground. I.sub.B is indicated on the current sensor/display 1320. A beam gate 1172 is controlled through a linkage 1338 by beam gate controller 1336. Beam gate controller 1336 may be manual or may be electrically or mechanically timed by a preset value to open the beam gate 1172 for a predetermined interval. In use, V.sub.D is set to zero, the beam current, I.sub.B, striking the workpiece holder is measured. Based on previous experience for a given GCIB process recipe, an initial irradiation time for a given process is determined based on the measured current, I.sub.B. V.sub.D is increased until all measured beam current is transferred from I.sub.B to I.sub.D and I.sub.D no longer increases with increasing V.sub.D. At this point a Neutral Beam 1314 comprising energetic dissociated components of the initial GCIB 1128 irradiates the workpiece holder 1162. The beam gate 1172 is then closed and the workpiece 1160 placed onto the workpiece holder 1162 by conventional workpiece loading means (not shown). The beam gate 1172 is opened for the predetermined initial radiation time. After the irradiation interval, the workpiece may be examined and the processing time adjusted as necessary to calibrate the duration of Neutral Beam processing based on the measured GCIB beam current I.sub.B. Following such a calibration process, additional workplaces may be processed using the calibrated exposure duration.
[0087] The Neutral Beam 1314 contains a repeatable fraction of the initial energy of the accelerated GCIB 1128. The remaining ionized portion 1316 of the original GCIB 1128 has been removed from the Neutral Beam 1314 and is collected by the grounded deflection plate 1304. The ionized portion 1316 that is removed from the Neutral Beam 1314 may include monomer ions and gas cluster ions including intermediate size gas cluster ions. Because of the monomer evaporation mechanisms due to cluster heating during the ionization process, intra-beam collisions, background gas collisions, and other causes (all of which result in erosion of clusters) the Neutral Beam substantially consists of neutral monomers, while the separated charged particles are predominately cluster ions. The inventors have confirmed this by suitable measurements that include re-ionizing the Neutral Beam and measuring the charge to mass ratio of the resulting ions. As will be shown below, certain superior process results are obtained by processing workpieces using this Neutral Beam.
[0088] FIG. 4 is a schematic of a Neutral Beam processing apparatus 1400 as may, for example, be used in generating Neutral Beams as may be employed in embodiments of the invention. It uses a thermal sensor for Neutral Beam measurement. A thermal sensor 1402 attaches via low thermal conductivity attachment 1404 to a rotating support arm 1410 attached to a pivot 1412. Actuator 1408 moves thermal sensor 1402 via a reversible rotary motion 1416 between positions that intercept the Neutral Beam 1314 or GCIB 1128 and a parked position indicated by 1414 where the thermal sensor 1402 does not intercept any beam. When thermal sensor 1402 is in the parked position (indicated by 1414) the GCIB 1128 or Neutral Beam 1314 continues along path 1406 for irradiation of the workpiece 1160 and/or workpiece holder 1162. A thermal sensor controller 1420 controls positioning of the thermal sensor 1402 and performs processing of the signal generated by thermal sensor 1402. Thermal sensor 1402 communicates with the thermal sensor controller 1420 through an electrical cable 1418. Thermal sensor controller 1420 communicates with a dosimetry controller 1432 through an electrical cable 1428. A beam current measurement device 1424 measures beam current I.sub.B flowing in electrical lead 1168 when the GCIB 1128 strikes the workpiece 1160 and/or the workpiece holder 1162. Beam current measurement device 1424 communicates a beam current measurement signal to dosimetry controller 1432 via electrical cable 1426. Dosimetry controller 1432 controls setting of open and closed states for beam gate 1172 by control signals transmitted via linkage 1434. Dosimetry controller 1432 controls deflector power supply 1440 via electrical cable 1442 and can control the deflection voltage V.sub.D between voltages of zero and a positive voltage adequate to completely deflect the ionized portion 1316 of the GCIB 1128 to the deflection plate 1304. When the ionized portion 1316 of the GCIB 1128 strikes deflection plate 1304, the resulting current I.sub.D id measured by current sensor 1422 and communicated to the dosimetry controller 1432 via electrical cable 1430. In operation dosimetry controller 1432 sets the thermal sensor 1402 to the parked position 1414, opens beam gate 1172, sets V.sub.D to zero so that the full GCIB 1128 strikes the workpiece holder 1162 and/or workpiece 1160. The dosimetry controller 1432 records the beam current I.sub.B transmitted from beam current measurement device 1424. The dosimetry controller 1432 then moves the thermal sensor 1402 from the parked position 1414 to intercept the GCIB 1128 by commands relayed through thermal sensor controller 1420. Thermal sensor controller 1420 measures the beam energy flux of GCIB 1128 by calculation based on the heat capacity of the sensor and measured rate of temperature rise of the thermal sensor 1402 as its temperature rises through a predetermined measurement temperature (for example 70 degrees C.) and communicates the calculated beam energy flux to the dosimetry controller 1432 which then calculates a calibration of the beam energy flux as measured by the thermal sensor 1402 and the corresponding beam current measured by the beam current measurement device 1424. The dosimetry controller 1432 then parks the thermal sensor 1402 at parked position 1414, allowing it to cool and commands application of positive V.sub.D to deflection plate 1302 until all of the current I.sub.D due to the ionized portion of the GCIB 1128 is transferred to the deflection plate 1304. The current sensor 1422 measures the corresponding I.sub.D and communicates it to the dosimetry controller 1432. The dosimetry controller also moves the thermal sensor 1402 from parked position 1414 to intercept the Neutral Beam 1314 by commands relayed through thermal sensor controller 420. Thermal sensor controller 420 measures the beam energy flux of the Neutral Beam 1314 using the previously determined calibration factor and the rate of temperature rise of the thermal sensor 1402 as its temperature rises through the predetermined measurement temperature and communicates the Neutral Beam energy flux to the dosimetry controller 1432. The dosimetry controller 1432 calculates a neutral beam fraction, which is the ratio of the thermal measurement of the Neutral Beam 1314 energy flux to the thermal measurement of the full GCIB 1128 energy flux at sensor 1402. Under typical operation, a neutral beam fraction of from about 5% to about 95% is achieved. Before beginning processing, the dosimetry controller 1432 also measures the current, I.sub.D, and determines a current ratio between the initial values of I.sub.B and I.sub.D. During processing, the instantaneous I.sub.D measurement multiplied by the initial I.sub.B/I.sub.D ratio may be used as a proxy for continuous measurement of the I.sub.B and employed for dosimetry during control of processing by the dosimetry controller 1432. Thus the dosimetry controller 1432 can compensate any beam fluctuation during workpiece processing, just as if an actual beam current measurement for the full GCIB 1128 were available. The dosimetry controller uses the neutral beam fraction to compute a desired processing time for a particular beam process. During the process, the processing time can be adjusted based on the calibrated measurement of I.sub.D for correction of any beam fluctuation during the process.
[0089] FIGS. 5A and 5B show comparative results of full GCIB and Neutral Beam processing of a drug film deposited on a cobalt-chrome coupon used to evaluate drug elution rate for a drug eluting coronary stent. FIG. 5A represents a sample irradiated using an argon GCIB (Including the charged and neutral components) accelerated using V.sub.Acc of 30 kV with an irradiated dose of 210.sup.15 gas cluster ions per cm.sup.2. FIG. 5B represents a sample irradiated using a Neutral Beam derived from an argon GCIB accelerated using V.sub.Acc of 30 kV. The Neutral Beam was irradiated with a thermal energy dose equivalent to that of a 30 kV accelerated, 210.sup.15 gas cluster ion per cm.sup.2 dose (equivalent determined by beam thermal energy flux sensor). The irradiation for both samples was performed through a cobalt chrome proximity mask having an array of circular apertures of approximately 50 microns diameter for allowing beam transmission. FIG. 5A is a scanning electron micrograph of a 300 micron by 300 micron region of the sample that was irradiated through the mask with full beam. FIG. 5B is a scanning electron micrograph of a 300 micron by 300 micron region of the sample that was irradiated through the mask with a Neutral Beam. The sample shown in FIG. 5A exhibits damage and etching caused by the full beam where it passed through the mask. The sample shown in FIG. 5B exhibits no visible effect. In elution rate tests in physiological saline solution, the samples processed like the FIG. B sample (but without mask) exhibited superior (delayed) elution rate compared to the samples processed like the FIG. 5A sample (but without mask). The results support the conclusion that processing with the Neutral Beam contributes to the desired delayed elution effect, while processing with the full GCIB (charged plus neutral components) contributes to weight loss of the drug by etching, with inferior (less delayed) elution rate effect.
[0090] To further illustrate the ability of an accelerated Neutral Beam derived from an accelerated GCIB to aid in attachment of a drug to a surface and to provide drug modification in such a way that it produces a barrier layer resulting in delayed drug elution, an additional test was performed. Silicon coupons approximately 1 cm by 1 cm (1 cm2) were prepared from highly polished clean semiconductor-quality silicon wafers for use as drug deposition substrates. A solution of the drug Rapamycin (Catalog number R-5000, LC Laboratories, Woburn, Mass. 01801, USA) was formed by dissolving 500 mg of Rapamycin in 20 ml of acetone. A pipette was then used to dispense approximately 5 micro-liter droplets of the drug solution onto each coupon. Following atmospheric evaporation and vacuum drying of the solution, this left approximately 5 mm diameter circular Rapamycin deposits on each of the silicon coupons. Coupons were divided into groups and either left un-irradiated (controls) or irradiated with various conditions of Neutral Beam irradiation. The groups were then placed in individual baths (bath per coupon) of human plasma for 4.5 hours to allow elution of the drug into the plasma. After 4.5 hours, the coupons were removed from the plasma baths, rinsed in deionized water and vacuum dried. Weight measurements were made at the following stages in the process: 1) pre-deposition clean silicon coupon weight; 2) following deposition and drying, weight of coupon pins deposited drug; 3) post-irradiation weight; and 4) post plasma-elution and vacuum drying weight. Thus for each coupon the following information is available: 1) initial weight of the deposited drug load on each coupon; 2) the weight of drug lost during irradiation of each coupon; and 3) the weight of drug lost during plasma elution for each coupon. For each irradiated coupon it was confirmed that drug loss during irradiation was negligible. Drug loss during elution in human plasma is shown in Table 1. The groups were as follows: Control Groupno irradiation was performed; Group 1irradiated with a Neutral Beam derived from a GCIB accelerated with a V.sub.Acc of 30 kV. The Group 1 irradiated beam energy dose was equivalent to that of a 30 kV accelerated, 510.sup.14 gas cluster ion per cm.sup.2 dose (energy equivalence determined by beam thermal energy flux sensor); Group 2irradiated with a Neutral Beam derived from a GCIB accelerated with a V.sub.Acc of 30 kV. The Group 2 irradiated beam energy dose was equivalent to that of a 30 kV accelerated. 110.sup.14 gas cluster ion per cm.sup.2 dose (energy equivalence determined by beam thermal energy flux sensor); and Group 3irradiated with a Neutral Beam derived from a GCIB accelerated with a V.sub.Acc of 25 kV. The Group 3 irradiated beam energy dose was equivalent to that of a 25 kV accelerated, 510.sup.14 gas cluster ion per cm.sup.2 dose (energy equivalence determined by beam thermal energy flux sensor).
TABLE-US-00001 TABLE 1 Group 1 Group 2 Group 3 Group [5 10.sup.14] [1 10.sup.14] [5 10.sup.14] [Dose] Control {30 kV} {30 kV} {25 kV} {V.sub.Acc} Start Elution Elution Start Elution Elution Start Elution Start Elution Elution Coupon Load Loss Loss Load Loss Loss Load Loss Loss Load Loss Loss # (g) (g) % (g) (g) % (g) (g) % (g) (g) % 1 83 60 72 88 4 5 93 10 11 88 0 2 87 55 63 100 7 7 102 16 16 82 5 6 3 88 61 69 83 2 2 81 35 43 93 1 1 4 96 72 75 93 7 8 84 3 4 Mean 89 62 70 90 4 5 92 17 19 87 2 3 5 7 9 3 9 13 5 2 p value 0.00048 0.014 0.00003
[0091] Table 1 shows that for every case of Neutral Beam irradiation (Groups 1 through 3), the drug lost during a 4.5-hour elution into human plasma was much lower than for the un-irradiated Control Group. This indicates that the Neutral Beam irradiation results in better drug adhesion and/or reduced elution rate as compared to the un-irradiated drug. The p values (heterogeneous unpaired T-test) indicate that for each of the Neutral Beam irradiated Groups 1 through 3, relative to the Control Group, the difference in the drug retention following elution in human plasma was statistically significant.
[0092] To confirm that complex molecules such as proteins are not destroyed by GCIB or Neutral Beam irradiation when layers containing them are treated to form barrier layers for controlling their release, evaluations were made using the bone morphogenic protein BMP2 in combination with GCIB and Neutral Beam irradiation and assays to determine protein degradation and protein loss.
[0093] Titanium foils were cut to 11 cm and cleaned in 70% isopropanol for 30 minutes followed by two 10 minute washes in double distilled water. Recombinant human protein BMP2 (rhBMP2) supplied from R&D Systems, Inc., 614 McKinley Place NE, Minneapolis, Minn. 55413, USA was reconstituted in 4 mM HCl at 100 ng/l. 18 Ti foils were spotted with 10 l BMP2 (1 l) and allowed to air dry for 1 hour. The 18 foils were divided into the following groups: 1) GCIB irradiated, 510.sup.14 ions/cm.sup.2 dose, low acceleration potential (n=3pieces); 2) GCIB irradiated, 510.sup.14 ions/cm.sup.2 dose, high acceleration potential (n=3 pieces); 3) Neutral Beam irradiated, 510.sup.14 ions/cm.sup.2 dose (thermal energy dose equivalent), low acceleration potential (n=3 pieces); 4) Neutral Beam irradiated, 510.sup.14 ions/cm.sup.2 dose (thermal energy dose equivalent), high acceleration potential (n=3 pieces). For each condition listed, n=1 piece was used for degradation silver stain assay and n=2 pieces were used for Enzyme-Linked Immunosorbent Assay (ELISA) tests. High acceleration potential was 30 kV, and low acceleration potential was 10 kV in each case.
[0094] Degradation assay: 1 cell lysis buffer from Cell Signaling Technology (#9803) with HALT protease inhibitor (Thermo Scientific #87786) was prepared according to manufacturer's instructions; 15 l was placed on the Ti foil and pipetted up and down 5 times to extract protein from surface and placed in Eppendorf micro tubes. As a control, pure protein, 5 l rhBMP2 (500 ng) was placed in a separate tube. To each tube, was added 15 l Laemmli sample buffer (Bio-Rad #161-0737) with 2-mercaptoethanol (Bio-Rad #161-0710) according to manufacturer's instructions, boiled 5 min, iced 2 min. Samples were loaded on 18% sodium dodecyl sulfate polyacrylamide electrophoresis gel and driven at 75V until dye front was near bottom (approximately 2 hours). The gel was removed and stained with silver stain (Bio-Rad #161-0449) per manufacturer's instructions.
[0095] Degradation assay results: GCIB and Neutral Beam at both high and low energies appeared to have no degredative effects on BMP2. Proteins extracted from the Ti foils appeared to match pure BMP2 protein in electrophoresis response. No degradation products were visible below BMP2 size (15-16 kDa). Any protein modified in the formation of the resulting barrier layer does not appear to be eluted as degradation product.
[0096] ELISA assay: An R&D Systems, Inc. Human BMP2 Quantikine ELISA kit was used to assay BMP2. To each Ti foil (see above), was added 500 l 1 lysis butter and was allowed to reside on the foil for 10 minutes followed by pipetting up and down 5 times to extract protein from surface and was placed in micro tubes. Manufacturer's instructions for the ELISA kit (R&D Systems #DBP200) were followed to perform the assay. Briefly, initial concentration was diluted 500 fold to fall within the range of the kit using 1 calibrator diluent. Duplicates from each sample were used and an initial n=2 per foil sample resulting in 4 individual assay reads per sample. A standard curve using BMP2 was generated and both standards and unknown concentrations of samples were placed on wells pre-conjugated with BMP2 monoclonal antibody against the full length BMP2 protein. Following binding to the wells, a conjugated anti-BMP2 bound to horseradish peroxidase was added to create a sandwich ELISA. A colorimetric substrate was added, and following color development, the color was measured on a colorimetric plate reader at 450 nm wavelength with background corrected at 570 nm. Concentrations of the samples were calculated from the standard curve.
[0097] ELISA assay results: Results revealed that Control samples, ie. samples not irradiated with GCIB or Neutral Beam recovered fully at 1.000.02 g BMP2. GCIB low-energy resulted in 0.800.03 g BMP2. GCIB high energy recovery was at 0.710.10 g BMP2. Neutral Beam low energy resulted in 0.700.14 g BMP2 and Neutral Beam high energy recovery was 0.700.02 g BMP2. As the antibody against the BMP2 is against the full length protein, the amount recovered represents the amount of active BMP2 present. It is believed that the amounts lost may be in part due to vacuum sublimation in the GCIB/Neutral Beam tool, the actual GCIB or Neutral Beam irradiation process, and loss due to the resulting modification of BMP2 to form the resulting barrier layer, which is not active protein.
[0098] Reference is now made to FIG. 6, which shows a view 100 of a prior art bone-implantable medical device in the form of a prior art dental implant 102. The prior art dental implant 102 is used for insertion into and implantation into a hole in a jawbone to form a basis for attaching a dental prosthesis, such as a prosthetic tooth or a dental restoration, for example. Drilling or other surgical techniques are typically employed to form the jawbone hole. The prior art dental implant 102 has a post 110 for attachment of a dental prosthesis (not shown). It has an implantable portion consisting of a threaded portion 104 and an unthreaded portion 106. A neck 108 connects the implantable portion with the post 110. The prior art dental implant 102 may be a single piece, or a composite of two or more pieces joined by any of a variety of known fastening techniques. In general the materials of the outer surfaces of the implantable portion are formed from biocompatible materials, often metal, oxide, or ceramic, preferably titanium with a titania (native or otherwise) surface or zirconia. Prior art dental implants are manufactured according to numerous different configurations, but in general they all have an implantable portion intended to be implanted into a hole or otherwise attached to a bone. The prior art dental implant 102 has a threaded portion 104 intended to intimately engage a hole in a bone, where if the implant is successful, it eventually becomes integrated with the bone by regrowth of new bone material.
[0099] FIG. 7 A is a view 200A of a bone-implantable medical device in the form of a dental implant 202 as may be employed in an embodiment of the present invention. Dental implant 202 is an improved form of the prior art dental implant 102 (as shown in FIG. 6). Referring again to FIG. 7A, the implantable portion of the dental implant 202 preferably has a titania surface and has a multiplicity of holes (examples indicated by 204, not all holes labeled). Although shown in a particular pattern for explaining the invention, the particular pattern shown is not essential to the invention and it is understood that many and varied patterns can be employed in various embodiments of the invention. The relative sizes of the dental implant 202 and the holes 204 are not necessarily shown to scale. The holes may have a wide range of sizes and shapes. The holes 204 can be formed by a variety of techniques, but the methods of laser machining and focused ion beam machining are preferable because they can be controlled with great precision and can produce small, deep holes. The holes 204 may be, for example from about 50 micrometers to about 500 micrometers in diameter (or width) and may have an aspect ratio (diameter or width to depth) of about 0.5 to about 10 or even more. The holes 204 may be circular as indicated in FIG. 7 or in the form of grooves, trenches, other shapes, or combinations. The holes 204 may be of a variety of different diameters (or widths) and aspect ratios and (if grooves or trenches) lengths and shapes, so as to have differing volumes. The holes 204, empty at this process step, are provided for holding one or more therapeutic agents as for example BMP and/or antibiotics, anti-inflammatory agents, etc.
[0100] FIG. 7B is a view 200B of the dental implant 202, after additional processing according to an embodiment of the invention. A portion of the surface of the denial implant is shown as coated with an osteoinductive agent, for example HA. The coated surface portion 210 (indicated in the figure by coarse stippling), in this case corresponds with the surface of the implantable portion of the dental implant 202, but could alternatively be one or more smaller regions of the implantable portion of the dental implant 202, with other regions uncoated. The osteoinductive agent coating may be applied by any of several methods, including for examples, spraying or suspension of ultra-fine particles, precipitation from solution, dipping, electrostatic deposition, ultrasonic spraying, plasma spraying, and sputter coating. During coating, a conventional masking scheme may be employed to limit deposition to a selected location or locations. A coating thickness of from about 0.01 to about 5 micrometers may preferably be utilized. At this step of the process, the coating of osteoinductive agent is still susceptible to the problems described aboveit can be abraded away or otherwise undesirably removed during the mechanical stresses of implantation into bone.
[0101] FIG. 7C shows a view 200C of the dental implant 202 after a portion of the surface has been coated with osteoinductive agent. An ion beam, preferably GCIB 220 is now employed to irradiate the coated surface portion 210 of the dental implant 202 to form a thin osteoinductive agent-infused layer in the preferably titania or zirconia surface of the implantable portion of the dental implant 202 wherever the coated surface portion 210 previously existed. However, if for any reason it is not desired to form an osteoinductive agent-infused layer at any portion of the osteoinductive agent-coated surface, a conventional masking scheme or controlled direction of the GCIB 220 may be employed to limit irradiation to selected locations. Although the infused layer has been described, for example, as an HA-infused layer it will be readily understood, that if a different osteoinductive agent is used to form the coated surface portion 210, then the infused layer will be an infused layer of the different agent. In infusing the osteoinductive agent into the surface of the dental implant 202, a GCIB 220 comprising preferably argon cluster ions or oxygen cluster ions may be employed. The GCIB 220 may be accelerated with an accelerating potential of from 5 kV to 70 kV or more. The coating may be exposed to a GCIB dose of at least about 110.sup.14 gas cluster ions per square centimeter. The GCIB irradiation step produces an osteoinductive agent-infused layer within the immediate surface of the titania or zirconia that is on the order of from about 1 to about 10 nanometers thick. While performing the ion beam irradiation, it is preferable to rotate the dental implant 202 about its axis with a rotary motion 222 during irradiation to assure that the desired ion dose is achieved on the entire coated surface portion 210. U.S. Pat. No. 6,676,989C1 issued to Kirkpatriek et al. teaches a GCIB processing system having a holder and manipulator suited for rotary processing tubular or cylindrical workpieces such as vascular stents and with routine adaptation, that system is also capable of the rotary irradiation required for this invention. In certain cases it may be desirable to infuse larger quantities of osteoinductive agent than can conveniently be done in a single coating and GCIB irradiation. In such cases, it is within the scope of the invention to repeat (one or more times) the steps of (a) coating the desired areas of the dental implant 202 with osteoinductive agent, and (b) irradiating the coated areas with GCIB to infuse the additional osteoinductive agent (using the techniques described herein in the descriptions of FIGS. 2B and 2C.
[0102] FIG. 7D shows a view 200D of the dental implant 202 following the HA infusion step. The osteoinductive agent-coated portion has been fully converted to an osteoinductive agent-infused surface region 230 according to an embodiment of the invention.
[0103] FIG. 7E shows a view 200E of a dental implant 202, having an osteoinductive agent infused surface region. At this step, the holes 204 (as shown in FIG. 2A) are now loaded with a therapeutic material, forming loaded holes 240 (again referring to FIG. 7E). The loading of the therapeutic material may be done by any of numerous methods, including spraying, dipping, wiping, electrostatic deposition, ultrasonic spraying, vapor deposition, or by discrete droplet-on-demand fluid jetting technology. When spraying, dipping, wiping, electrostatic deposition, ultrasonic spraying, vapor deposition, or similar techniques are employed, a conventional masking scheme may be beneficially employed to limit deposition to a hole or to several or all of the holes in the dental implant 202. For liquids and solutions, discrete droplet-on-demand fluid-jetting is a preferred deposition method because it provides the ability to introduce precise volumes of liquid materials or solutions into precisely programmable locations. Discrete droplet-on-demand fluid jetting may be accomplished using commercially available fluid-jet print head jetting devices as are available (for example, not limitation) from MicroFab Technologies, Inc., of Plano, Tex. When the therapeutic material is a liquid, liquid suspension, or a solution, it is preferably dried or otherwise hardened before proceeding to the next step. The drying or hardening step may include baking, low temperature baking, or vacuum evaporation, as examples.
[0104] FIG. 7F is a view 200F showing an ion irradiation step in the formation of a thin barrier layer in the surface of the therapeutic agent loaded in the holes in the dental implant 202. An ion beam, preferably GCIB 250 is now employed to irradiate the surface of the therapeutic agent in the loaded holes 240 (see FIG. 7E) in the dental implant 202 to form a thin barrier layer at the surface to the therapeutic agent, forming loaded holes with thin barrier layers 254 at the exposed surface. The GCIB 250 forms a thin barrier layer at the surface of the therapeutic agent in the holes by modification of a thin upper region of the therapeutic agent. The thin barrier layer consists of therapeutic agent modified so as to densify, carbonize or partially carbonize, denature, cross-link, or polymerize molecules of the therapeutic material in the thin uppermost layer of the therapeutic material. The thin barrier layer may have a thickness on the order of about 10 nanometers or even less. Additional details on the thin barrier layer and the process of its formation are described hereinafter in the discussion of FIGS. 3C and 3D.
[0105] FIGS. 3A, 3B, 3C, and 3D show detail of the steps for loading holes in a bone-implantable medical device with a therapeutic agent, and forming a thin barrier layer thereon for controlling retention and elution of the therapeutic agent by using GCIB irradiation.
[0106] FIG. 8 A shows a view 300A of a portion 304 of a surface 302 of a dental implant 202 (as shown in at the stage indicated in FIG. 7D, i.e., having an osteoinductive agent-infused surface region according to the invention), wherein the surface 302 represents a portion of the osteoinductive agent-infused surface region. Again referring to FIG. 8A, the portion 304 of the surface 302 of the dental implant 202 has a hole 204 having a diameter 306 and a depth 308. In this instance the hole 204 is intended to represent a substantially cylindrical hole, but as previously explained, other hole configurations are expected within the scope of the invention and the cylindrical nature of the hole is not intended to be limiting, but rather for clear explanation of the invention. The hole 204 is at a stage of readiness for loading with a therapeutic agent.
[0107] FIG. 5B shows a view 300B of a portion 304 of a surface 302 of a dental implant 202 with an osteoinductive agent-infused surface region. In this stage, the hole 204 has been loaded with a therapeutic agent 310, forming a loaded hole 240, corresponding to the loaded hole of FIG. 7E.
[0108] FIG. 8C shows a view 300C of a portion 304 of a surface 302 of a dental implant 202 with an osteoinductive agent-infused surface region and a loaded hole 240 loaded with therapeutic agent 310. An ion beam, preferably GCIB 250 is directed at the surface of the therapeutic agent 310 for the purpose of modifying the uppermost part of the surface of the therapeutic agent 310 to form a barrier layer. The therapeutic agent 310 is irradiated by the GCIB 250 modify of a thin upper region of the surface of the therapeutic agent 310. In modifying the surface, a GCIB 250 comprising preferably argon cluster ions or cluster ions of another inert gas may be employed. The GCIB 250 is may be accelerated with an accelerating potential of from 5 kV to 50 kV or more. The upper surface of the therapeutic agent 310 is may be exposed to a GCIB dose of at least about 110.sup.13 gas cluster ions per square centimeter.
[0109] FIG. 8D shows a view 300D of a portion 304 of a surface 302 of a dental implant 202 with an osteoinductive agent-infused surface region and a hole 254 that is loaded with a therapeutic agent 310 upon which has been formed a thin barrier layer 320 by ion irradiation of the uppermost surface of the therapeutic agent 310. The thin barrier layer 320 consists of therapeutic agent 310 modified so as to density, carbonize or partially carbonize, denature, cross-link, or polymerize molecules of the therapeutic agent in the thin uppermost layer of the therapeutic agent 310. The thin barrier layer 320 may have a thickness on the order of about 10 nanometers or even less. By selecting the dose and/or accelerating potential of the GCIB 250 (FIGS. 2F and 3C), the characteristics of the thin barrier layer 320 may be adjusted to permit control of the elution rate and/or the rate of inward diffusion of water and/or other biological fluids when the dental implant 202 is implanted in bone. In general, increasing acceleration potential increases the thickness of the thin barrier layer that is formed, and modifying the GCIB dose changes the nature of the thin barrier layer by changing the degree of cross linking, densification, carbonization, denaturization, and/or polymerization that results. This provides means to control the rate at which the therapeutic agent 310 will subsequently release or elute through the barrier and/or the rate at which water and/or biological fluids may diffuse into the drug from outside the dental implant 202.
[0110] FIG. 9 shows a bone-implantable medical device in the form of an artificial hip joint prosthesis 400 for replacement of a femoral ball. The prosthesis 400 has a ball 402 for replacement of the ball portion of the natural joint and has a stem 404 for insertion into and for integration with the femur. According to the invention, a portion 408 of the surface of the stem 404 has been osteoinductive agent-infused by osteoinductive agent-coating followed by ion irradiation (preferably GCIB irradiation) and has a pattern of holes 406 that are loaded with a therapeutic agent and which have been ion irradiated (preferably GCIB irradiated) to form thin barrier layers for control of elution rate of the therapeutic agent.
[0111] FIG. 10 shows a cross sectional view 700 of the surface 704 of a portion 702 of a bone-implantable medical device having a variety of therapeutic agent loaded holes 706, 708, 710, 712, and 714 shown to point out the diversity and flexibility of the invention. The bone-implantable medical device could, for example, be any of a dental implant, a bone screw, an artificial joint prosthesis, or any other bone-implantable medical device. The holes all have thin barrier layers 740 formed according to the invention on one or more layers of therapeutic agent in each hole. For simplicity, not all of the thin barrier layers in FIG. 10 are labeled with reference numerals, but hole 714 is shown containing a first therapeutic agent 736 covered with a thin barrier layer 740 (only thin barrier layer 740 in hole 714 is labeled with a reference numeral, but each cross-hatched region in FIG. 10 indicates a thin barrier layer, and all will hereinafter be referred to by the exemplary reference numeral 740). Hole 706 contains a second therapeutic agent 716 covered with a thin barrier layer 740. Hole 708 contains a third therapeutic agent 720 covered with a thin barrier layer 740. Hole 710 contains a fourth therapeutic agent 738 covered with a thin barrier layer 740. Hole 712 contains fifth, sixth, and seventh therapeutic agents 728, 726, and 724, each respectively covered with a thin barrier layer 740. Each of the respective therapeutic agents 716, 720, 724, 726, 728, 736, and 738 may be selected to be a different therapeutic agent material or may be the same therapeutic agent materials in various combinations of different or same. Each of the thin barrier layers 740 may have the same or different properties for controlling elution or release rate and/or for controlling the rate of inward diffusion of water or other biological fluids according to ion beam processing (preferably GCIB processing) principles discussed herein above. Holes 706 and 708 have the same widths and fill depth 718, and thus hold the same volume of therapeutic agents, but the therapeutic agents 716 and 720 may be different therapeutic agents for different therapeutic modes. The thin barrier layers 740 corresponding respectively to holes 706 and 708 may have either same or differing properties for providing same or different elution, release, or inward diffusion rates for the therapeutic agents contained in holes 706 and 708. Holes 708 and 710 have the same widths, but differing fill depths, 718 and 722 respectively, thus containing differing therapeutic agent loads corresponding to differing doses. The thin barrier layers 740 corresponding respectively to holes 708 and 710 may have either same or differing properties for providing same or different elution, release, or inward diffusion rates for the therapeutic agents contained in holes 708 and 710. Holes 710 and 712 have the same widths 730, and have the same fill depths 722, thus containing the same total therapeutic agent loads, but hole 710 is filled with a single layer of therapeutic agent 738, while hole 712 is filled with multiple layers of therapeutic agent 724, 726, and 728, which may each be the same or different volumes of therapeutic agent representing the same or different doses and furthermore may each be different therapeutic agent materials for different therapeutic modes. Each of the thin barrier layers 740 for holes 710 and 712 may have the same or different properties for providing same or different elution, release, or inward diffusion rates for the therapeutic agents contained in the holes. Holes 708 and 714 have the same fill depths 718, but have different widths and thus contain different volumes and doses of therapeutic agents 720 and 736. The thin barrier layers 740 corresponding respectively to holes 708 and 714 may have either same or differing properties for providing same or different elution, release, or inward diffusion rates for the therapeutic agents contained in holes 708 and 714. The overall hole (size, shape, and location) pattern on the surface 704 of the implantable medical device and the spacing between holes 732 may additionally be selected to control distribution of therapeutic agent dose across the surface of the implantable medical device. Thus there are many flexible options in the application of the invention for controlling the types and doses and dose distributions and release sequences and release rates of therapeutic agents contained in the bone-implantable medical devices of the invention.
[0112] Although the invention has been described with respect to formation of exemplary HA-infused layers, it is recognized that other osteoinductive agents can equally well be employed in forming the infused layers within the scope of the invention. Although the invention has particularly been described in terms of application to titanium (with titania surface) and zirconia dental implants, it is recognized that the scope of the invention includes bone-implantable medical devices constructed of a wide variety of other materials such as, for example polyether ether ketone (PEEK). In the case of electrically insulating materials such as PEEK, the accelerated Neutral Beam has the advantage of reduced damage in the insulating substrate as compared to a GCIB or other ion beam. Although the invention has been described with respect to various embodiments and applications in the field of bone-implantable medical devices (dental implants, joint prostheses, etc.), it is understood by the inventors that its application is not limited to that field and that the concepts of accelerated Neutral Beam infusion of surface coating materials into the surfaces upon which they reside has broader application in fields that will be apparent to those skilled in the art. It should be realized that this invention is also capable of a wide variety of further and other embodiments within the spirit and scope of the invention and the appended claims.
[0113] What is claimed is:
