Patent Publication Number: US-2019171098-A1

Title: Drug delivery system and method of manufacturing thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is continuation-in-part of co-pending U.S. patent application Ser. No. 14/238,364 filed on Sep. 26, 2014 and entitled DRUG DELIVERY SYSTEM AND METHOD OF MANUFACTURING THEREOF, which in turn is a U.S. national stage application under 35 U.S.C. 371 of International Application No. PCT/US2012/051801 filed on Aug. 22, 2012 and entitled DRUG DELIVERY SYSTEM AND METHOD OF MANUFACTURING THEREOF, which in turn claims priority to and benefit of U.S. Provisional Patent Application No. 61/526,171, filed on Aug. 22, 2011, which is incorporated by reference herein in its entirety for all purposes. 
     Further, this application is a continuation-in-part of co-pending U.S. patent application Ser. No. 14/496,412 filed on Sep. 25, 2014 and entitled METHOD AND APPARATUS FOR NEUTRAL BEAM PROCESSING BASED ON GAS CLUSTER ION BEAM TECHNOLOGY, which in turn is a divisional of U.S. application Ser. No. 13/215,514, filed on Aug. 23, 2011 and entitled METHOD AND APPARATUS FOR NEUTRAL BEAM PROCESSING BASED ON GAS CLUSTER ION BEAM TECHNOLOGY, now U.S. Pat. No. 8,847,148, which in turn claims priority to and benefit of U.S. Provisional Patent Application No. 61/376,225, filed Aug. 23, 2010, U.S. Provisional Patent Application No. 61/490,675, filed May 27, 2011, U.S. Provisional Patent Application No. 61/473,359, filed Apr. 8, 2011, and U.S. Provisional Patent Application No. 61/484,421, filed May 10, 2011, all of which are incorporated herein by reference in their entirety for all purposes. 
    
    
     FIELD OF THE INVENTION 
     This invention relates generally to drug delivery systems such as, for example, medical devices implantable in a mammal (e.g., coronary stents, prostheses, etc.), and more specifically to a system and method for controlling the surface characteristics of such drug delivery systems such as, for example, the drug release rate, binding of the drug to the surface of the medical device, and bio-reactivity. Additionally, it relates to surface treatment through the use of a neutral gas cluster beam and/or a neutral monomer beam either of which may be derived from a gas cluster ion beam (GCIB). 
     BACKGROUND OF THE INVENTION 
     A coronary stent is an implantable medical device that is used in combination with balloon angioplasty. Balloon angioplasty is a procedure used to treat coronary atherosclerosis. Balloon angioplasty compresses built-up plaque against the walls of the blocked artery by the inflation of a balloon at the tip of a catheter inserted into the artery during the angioplasty procedure. Unfortunately, the body&#39;s response to this procedure often includes thrombosis or blood clotting and the formation of scar tissue or other trauma-induced tissue reactions at the treatment site. Statistics show that restenosis or re-narrowing of the artery by scar tissue after balloon angioplasty occurs in up to 35 percent of the treated patients within only six months after these procedures, leading to severe complications in many patients. 
     To reduce restenosis, cardiologists are now often placing small tubular devices of various forms, such as wire mesh; expandable metal; and non-degradable and biodegradable polymers called a coronary stent at the site of blockage during balloon angioplasty. The goal is to have the stent act as a scaffold to keep the coronary artery open after the removal of the balloon. 
     However, there are also serious complications associated with the use of coronary stents. Coronary restenotic complications associated with stents occur in 16 to 22 percent of all cases within six months after insertion of the stent and are believed to be caused by many factors acting alone or in combination. These complications could be reduced by several types of drugs introduced locally at the site of stent implantation. Because of the substantial financial costs associated with treating the complications of restenosis, such as catheterization, restenting, intensive care, etc., a reduction in restenosis rates would save money and reduce patient suffering. 
     Numerous studies suggest that the current popular designs of coronary stents are functionally equivalent. Although the use of coronary stents is growing, the benefits of their use remain controversial in certain clinical situations or indications due to their potential complications. It is widely held that during the process of expanding the stent, damage occurs to the endothelial lining of the blood vessel triggering a healing response that re-occludes the artery. To help combat that phenomenon, drug-coated stents have been introduced to the market to help control the abnormal cell growth associated with this healing response. These drugs are typically mixed with a liquid polymer and applied to the stent surface. The polymer coating can include several layers such as the above drug containing layer as well as a drug free encapsulating layer, which can help to reduce the initial drug release amount caused by initial exposure to liquids when the device is first implanted. A further base coating of polymer located beneath the drug bearing layer is also known. One example of this arrangement used on stainless steel stents includes a base layer of Paralene C. and a drug/polymer mixture including polyethylene-co-vinyl acetate (PEVA) and poly n-butyl methacrylate (PBMA) in a two to one ratio, along with an non-drug impregnated top layer of the same mixture of PEVA and PBMA. One drug used is Sirolimus, a relatively new immunosuppressant drug also known as Rapamycin. Several other drug/polymer combinations exist from several manufactures. 
     In other applications, drugs have been applied to bare metal objects or polymer objects intended for medical implant (for example stents) and the drug adhesion to the object has been improved by GCIB irradiation. In still other applications, drug coatings on objects intended fro medical implant (again for example stents) have been treated with GCIB to modify the surface of the drug coating to modify the surface to form a barrier layer by direct transformation of a thin surface layer of the drug itself delay or otherwise favorable affect the elution characteristics of the drug when implanted In such cases where the medical device intended for implant consists only of biocompatible metals and a therapeutic drug coating, adhered or modified by GCIB irradiation, the ability to avoid entirely the use of a polymer to bind, attach, or delay elution of the drug has advantages for improving medical outcomes. Instances of polymer flaking, toxicity, and other undesired side effects of polymer use are avoided, while still providing effective drug eluting metal implants. However as will be discussed herein, there are some disadvantages to the use of GCIB processing on drug and/or polymer surfaces, that may be avoided by the invention. 
     Ions have long been favored for many processes because their electric charge facilitates their manipulation by electrostatic and magnetic fields. This introduces great flexibility in processing. However, in some applications, the charge that is inherent to any ion (including gas cluster ions in a GCIB) may produce undesirable effects in the processed surfaces. GCIB has a distinct advantage over conventional ion beams in that a gas cluster ion with a single or small multiple charge enables the transport and control of a much larger mass-flow (a cluster may consist of hundreds or thousands of molecules) compared to a conventional ion (a single atom, molecule, or molecular fragment.) Particularly in the case of electrically insulating materials and materials having high electrical resistivity, such as the surfaces of many drug coatings or many polymers, or many drug-polymer mixtures, surfaces processed using ions often suffer from charge-induced damage resulting from abrupt discharge of accumulated charges, or production of damaging electrical field-induced stress in the material (again resulting from accumulated charges). In many such cases, GCIBs have an advantage due to their relatively low charge per mass, but in some instances may not eliminate the target-charging problem. Furthermore, moderate to high current intensity ion beams may suffer from a significant space charge-induced defocusing of the beam that tends to inhibit transporting a well-focused beam over long distances. Again, due to their lower charge per mass relative to conventional ion beams, GCIBs have an advantage, but they do not fully eliminate the space charge transport problem. 
     A further instance of need or opportunity arises from the fact that although the use of beams of neutral molecules or atoms provides benefit in some surface processing applications and in space charge-free beam transport, it has not generally been easy and economical to produce intense beams of neutral molecules or atoms except for the case of nozzle jets, where the energies are generally on the order of a few milli-electron-volts per atom or molecule, and thus have limited processing capabilities. More energetic neutral particles can be beneficial or necessary in many applications, for example when it is desirable to break surface or shallow subsurface bonds to facilitate cleaning, etching, smoothing, deposition, amorphization, or to produce surface chemistry effects. In such cases, energies of from about an eV up to a few thousands of eV per particle can often be useful. Methods and apparatus for forming such Neutral Beams by first forming an accelerated charged GCIB and then neutralizing or arranging for neutralization of at least a fraction of the beam and separating the charged and uncharged fractions are disclosed herein. The Neutral Beams may consist of neutral gas clusters, neutral monomers, or a combination of both. Although GCIB processing has been employed successfully for many applications, there are new and existing application needs, especially in relation to processing drug coatings for forming drug eluting medical devices, not fully met by GCIB or other state of the art methods and apparatus, and wherein accelerated Neutral Beams may provide superior results. For example, in many situations, while a GCIB can produce dramatic atomic-scale smoothing of an initially somewhat rough surface, the ultimate smoothing that can be achieved is often less than the required smoothness, and in other situations GCIB processing can result in roughening moderately smooth surfaces rather than smoothing them further. 
     In view of the importance of in situ drug delivery, it is desirable to have control over the drug release rate from the implantable device as well as control over other surface characteristics of the drug delivery medium and to accomplish such control without damage to the drug or any insulating materials or high electrical resistivity materials that may be present in the device. 
     It is therefore an object of this invention to provide a means of controlling surface characteristics of a drug eluting material using accelerated Neutral Beam technology. 
     It is a further object of this invention to improve the functional characteristics of known in situ drug release mechanisms using accelerated Neutral Beam technology. 
     SUMMARY OF THE INVENTION 
     The objects set forth above as well as further and other objects and advantages of the present invention are achieved by the invention described herein below. The present invention is directed to the use of Neutral Beam processing of materials (including drugs) attached to surfaces (including surfaces of medical devices intended for surgical implant) to modify and delay or otherwise improve the rate at which the materials are released from the surface (as for example by elution, evaporation, or sublimation). In the case of implantable drug coated medical devices, the release mechanism is normally by elution. 
     Beams of energetic conventional ions, accelerated electrically charged atoms or molecules, are widely utilized to form semiconductor device junctions, to modify surfaces by sputtering, and to modify the properties of thin films. Unlike conventional ions, gas cluster ions are formed from clusters of large numbers (having a typical distribution of several hundreds to several thousands with a mean value of a few thousand) of weakly bound atoms or molecules of materials that are gaseous under conditions of standard temperature and pressure (commonly oxygen, nitrogen, or an inert gas such as argon, for example, but any condensable gas can be used to generate gas cluster ions) with each cluster sharing one or more electrical charges, and which are accelerated together through large electric potential differences (on the order of from about 3 kV to about 70 kV or more) to have high total energies. After gas cluster ions have been formed and accelerated, their charge states may be altered or become altered (even neutralized) by collisions with other cluster ions, other neutral clusters, or residual background gas particles, and thus they may fragment or may be induced to fragment into smaller cluster ions or into monomer ions and/or into neutralized smaller clusters and neutralized monomers, but the resulting cluster ions, neutral clusters, and monomer ions and neutral monomers tend to retain the relatively high velocities and energies that result from having been accelerated through large electric potential differences, with the accelerated gas cluster ion energy being distributed over the fragments. 
     As used herein, the terms “GCIB”, “gas cluster ion beam” and “gas cluster ion” are intended to encompass not only ionized beams and ions, but also accelerated beams and ions that have had all or a portion of their charge states modified (including neutralized) following their acceleration. The terms “GCIB” and “gas cluster ion beam” are intended to encompass all beams that comprise accelerated gas cluster ions even though they may also comprise non-clustered particles. As used herein, the term “Neutral Beam” is intended to mean a beam of neutral gas clusters and/or neutral monomers derived from an accelerated gas cluster ion beam and wherein the acceleration results from acceleration of a gas cluster ion beam. As used herein, the term “monomer” refers equally to either a single atom or a single molecule. The terms “atom,” “molecule,” and “monomer” may be used interchangeably and all refer to the appropriate monomer that is characteristic of the gas under discussion (either a component of a cluster, a component of a cluster ion, or an atom or molecule). For example, a monatomic gas like argon may be referred to in terms of atoms, molecules, or monomers and each of those terms means a single atom. Likewise, in the case of a diatomic gas like nitrogen, it may be referred to in terms of atoms, molecules, or monomers, each term meaning a diatomic molecule. Furthermore a molecular gas like CO 2 , may be referred to in terms of atoms, molecules, or monomers, each term meaning a three atom molecule, and so forth. These conventions are used to simplify generic discussions of gases and gas clusters or gas cluster ions independent of whether they are monatomic, diatomic, or molecular in their gaseous form. 
     As used herein, the term “drug” is intended to mean a therapeutic agent or a material that is active in a generally beneficial way, which can be released or eluted locally in the vicinity of an implantable medical device to facilitate implanting (for example, without limitation, by providing lubrication) the device, or to facilitate (for example, without limitation, through biological or biochemical activity) a favorable medical or physiological outcome of the implantation of the device. “Drug” is not intended to mean a mixture of a drug with a polymer that is employed for the purpose of binding or providing coherence to the drug, attaching the drug to the medical device, or for forming a barrier layer to control release or elution of the drug. A drug that has been modified by beam irradiation to densify, carbonize or partially carbonize, molecules of the drug is intended to be included in the “drug” definition. 
     As used herein, the term “elution” is intended to mean the release of an at least somewhat soluble drug material from a drug source on a medical device or in a hole in a medical device by gradual solution of the drug in a solvent, typically a bodily fluid solvent encountered after implantation of the medical device in a subject. In many cases the solubility of a drug material is high enough that the release of the drug into solution occurs more rapidly than desired, undesirably shortening the therapeutic lifetime of the drug following implantation of the medical device. The rate of elution or rate of release of the drug may depend on many factors such as for examples, solubility of the drug or exposed surface area between the drug and the solvent or mixture of the drug with other materials to reduce solubility. However, barrier or encapsulating layers between the drug and solvent can also modify the rate of elution or release of the drug. It is often desirable to delay the rate of release by elution to extend the time of therapeutic influence at the implant site. The desired elution rates are well known per se to those working in the arts of the medical devices. The present invention enhances their control of those rates in the devices. See, e.g. http://www.news-medical.net/health/Drug-Eluting-Stent-Design.aspx (duration of elution). U.S. Pat. No. 3,641,237 teaches some specific drug elution rates. Haery et al., “Drug-eluting stents: The beginning of the end of restenosis?”, Cleveland Clinic Journal of Medicine, V71(10), (2004), includes some details of drug release rates for stents at pg. 818, Col. 2, paragraph 5. 
     When accelerated gas cluster ions are fully dissociated and neutralized, the resulting neutral monomers will have energies approximately equal to the total energy of the original accelerated gas cluster ion, divided by the number, N I , of monomers that comprised the original gas cluster ion at the time it was accelerated. Such dissociated neutral monomers will have energies on the order of from about 1 eV to tens or even as much as a few thousands of eV, depending on the original accelerated energy of the gas cluster ion and the size of the gas cluster at the time of acceleration. 
     Gas cluster ion beams are generated and transported for purposes of irradiating a workpiece according to known techniques. Various types of holders are known in the art for holding the object in the path of the GCIB for irradiation and for manipulating the object to permit irradiation of a multiplicity of portions of the object. Neutral Beams may be generated and transported for purposes of irradiating a workpiece according to techniques taught herein. 
     The present invention may employ a high beam purity method and system for deriving from an accelerated gas cluster ion beam an accelerated neutral gas cluster and/or preferably monomer beam that can be employed for a variety of types of surface and shallow subsurface materials processing and which is capable, for many applications, of superior performance compared to conventional GCIB processing. It can provide well-focused, accelerated, intense neutral monomer beams with particles having energies in the range of from about 1 eV to as much as a few thousand eV. This is an energy range in which it has heretofore been impractical with simple, relatively inexpensive apparatus to form intense neutral beams. 
     These accelerated Neutral Beams are generated by first forming a conventional accelerated GCIB, then partly or essentially fully dissociating it by methods and operating conditions that do not introduce impurities into the beam, then separating the remaining charged portions of the beam from the neutral portion, and subsequently using the resulting accelerated Neutral Beam for workpiece processing. Depending on the degree of dissociation of the gas cluster ions, the Neutral Beam produced may be a mixture of neutral gas monomers and gas clusters or may essentially consist entirely or almost entirely of neutral gas monomers. It is preferred that the accelerated Neutral Beam is a fully dissociated neutral monomer beam. 
     An advantage of the Neutral Beams that may be produced by the methods and apparatus of this invention, is that they may be used to process electrically insulating materials without producing damage to the material due to charging of the surfaces of such materials by beam transported charges as commonly occurs for all ionized beams including GCIB. For example, in semiconductor and other electronic applications, ions often contribute to damaging or destructive charging of thin dielectric films such as oxides, nitrides, etc. The use of Neutral Beams can enable successful beam processing of polymer, dielectric, and/or other electrically insulating or high electrical resistivity materials, coatings, and films in other applications where ion beams may produce undesired side effects due to surface or other charging effects. Examples include (without limitation) processing of corrosion inhibiting coatings, and irradiation cross-linking and/or polymerization of organic films. In other examples, Neutral Beam induced modifications of polymer or other dielectric materials (e.g. sterilization, smoothing, improving surface biocompatibility, and improving attachment of and/or control of elution rates of drugs) may enable the use of such materials in medical devices for implant and/or other medical/surgical applications. Further examples include Neutral Beam processing of glass, polymer, and ceramic bio-culture labware and/or environmental sampling surfaces where such beams may be used to improve surface characteristics like, for example, roughness, smoothness, hydrophilicity, and biocompatibility. 
     Since the parent GCIB, from which accelerated Neutral Beams may be formed by the methods and apparatus of the invention, comprises ions it is readily accelerated to desired energy and is readily focused using conventional ion beam techniques. Upon subsequent dissociation and separation of the charged ions from the neutral particles, the neutral beam particles tend to retain their focused trajectories and may be transported for extensive distances with good effect. 
     When neutral gas clusters in a jet are ionized by electron bombardment, they become heated and/or excited. This may result in subsequent evaporation of monomers from the ionized gas cluster, after acceleration, as it travels down the beamline. Additionally, collisions of gas cluster ions with background gas molecules in the ionizer, accelerator and beamline regions, also heat and excite the gas cluster ions and may result in additional subsequent evolution of monomers from the gas cluster ions following acceleration. When these mechanisms for evolution of monomers are induced by electron bombardment and/or collision with background gas molecules (and/or other gas clusters) of the same gas from which the GCIB was formed, no contamination is contributed to the beam by the dissociation processes that results in evolving the monomers. 
     There are other mechanisms that can be employed for dissociating (or inducing evolution of monomers from) gas cluster ions in a GCIB without introducing contamination into the beam. Some of these mechanisms may also be employed to dissociate neutral gas clusters in a neutral gas cluster beam. One mechanism is laser irradiation of the cluster-ion beam using infra-red or other laser energy. Laser-induced heating of the gas cluster ions in the laser irradiated GCIB results in excitement and/or heating of the gas cluster ions and causes subsequent evolution of monomers from the beam. Another mechanism is passing the beam through a thermally heated tube so that radiant thermal energy photons impact the gas cluster ions in the beam. The induced heating of the gas cluster ions by the radiant thermal energy in the tube results in excitement and/or heating of the gas cluster ions and causes subsequent evolution of monomers from the beam. In another mechanism, crossing the gas cluster ion beam by a gas jet of the same gas or mixture as the source gas used in formation of the GCIB (or other non-contaminating gas) results in collisions of monomers of the gas in the gas jet with the gas clusters in the ion beam producing excitement and/or heating of the gas cluster ions in the beam and subsequent evolution of monomers from the excited gas cluster ions. By depending entirely on electron bombardment during initial ionization and/or collisions (with other cluster ions, or with background gas molecules of the same gas(es) as those used to form the GCIB) within the beam and/or laser or thermal radiation and/or crossed jet collisions of non-contaminating gas to produce the GCIB dissociation and/or fragmentation, contamination of the beam by collision with other materials is avoided. 
     As a neutral gas cluster jet from a nozzle travels through an ionizing region where electrons are directed to ionize the clusters, a cluster may remain un-ionized or may acquire a charge state, q, of one or more charges (by ejection of electrons from the cluster by an incident electron). The ionizer operating conditions influence the likelihood that a gas cluster will take on a particular charge state, with more intense ionizer conditions resulting in greater probability that a higher charge state will be achieved. More intense ionizer conditions resulting in higher ionization efficiency may result from higher electron flux and/or higher (within limits) electron energy. Once the gas cluster has been ionized, it is typically extracted from the ionizer, focused into a beam, and accelerated by falling through an electric field. The amount of acceleration of the gas cluster ion is readily controlled by controlling the magnitude of the accelerating electric field. Typical commercial GCIB processing tools generally provide for the gas cluster ions to be accelerated by an electric field having an adjustable accelerating potential, V Acc , typically of, for example, from about 1 kV to 70 kV (but not limited to that range—V Acc  up to 200 kV or even more may be feasible). Thus a singly charged gas cluster ion achieves an energy in the range of from 1 to 70 keV (or more if larger V Acc  is used) and a multiply charged (for example, without limitation, charge state, q=3 electronic charges) gas cluster ion achieves an energy in the range of from 3 to 210 keV (or more for higher V Acc ). For other gas cluster ion charge states and acceleration potentials, the accelerated energy per cluster is qV Acc  eV. From a given ionizer with a given ionization efficiency, gas cluster ions will have a distribution of charge states from zero (not ionized) to a higher number such as for example 6 (or with high ionizer efficiency, even more), and the most probable and mean values of the charge state distribution also increase with increased ionizer efficiency (higher electron flux and/or energy). Higher ionizer efficiency also results in increased numbers of gas cluster ions being formed in the ionizer. In many cases, GCIB processing throughput increases when operating the ionizer at high efficiency results in increased GCIB current. A downside of such operation is that multiple charge states that may occur on intermediate size gas cluster ions can increase crater and/or rough interface formation by those ions, and often such effects may operate counterproductively to the intent of the processing. Thus for many GCIB surface processing recipes, selection of the ionizer operating parameters tends to involve more considerations than just maximizing beam current. In some processes, use of a “pressure cell” (see U.S. Pat. No. 7,060,989, to Swenson et al.) may be employed to permit operating an ionizer at high ionization efficiency while still obtaining acceptable beam processing performance by moderating the beam energy by gas collisions in an elevated pressure “pressure cell.” 
     With the present invention there is no downside to operating the ionizer at high efficiency—in fact such operation is sometimes preferred. When the ionizer is operated at high efficiency, there may be a wide range of charge states in the gas cluster ions produced by the ionizer. This results in a wide range of velocities in the gas cluster ions in the extraction region between the ionizer and the accelerating electrode, and also in the downstream beam. This may result in an enhanced frequency of collisions between and among gas cluster ions in the beam that generally results in a higher degree of fragmentation of the largest gas cluster ions. Such fragmentation may result in a redistribution of the cluster sizes in the beam, skewing it toward the smaller cluster sizes. These cluster fragments retain energy in proportion to their new size (N) and so become less energetic while essentially retaining the accelerated velocity of the initial unfragmented gas cluster ion. The change of energy with retention of velocity following collisions has been experimentally verified (as for example reported in Toyoda, N. et al., “Cluster size dependence on energy and velocity distributions of gas cluster ions after collisions with residual gas,”  Nucl. Instr . &amp;  Meth. in Phys. Research  B 257 (2007), pp 662-665). Fragmentation may also result in redistribution of charges in the cluster fragments. Some uncharged fragments likely result and multi-charged gas cluster ions may fragment into several charged gas cluster ions and perhaps some uncharged fragments. It is understood by the inventors that design of the focusing fields in the ionizer and the extraction region may enhance the focusing of the smaller gas cluster ions and monomer ions to increase the likelihood of collision with larger gas cluster ions in the beam extraction region and in the downstream beam, thus contributing to the dissociation and/or fragmenting of the gas cluster ions. 
     In an embodiment of the present invention, background gas pressure in the ionizer, acceleration region, and beamline may optionally be arranged to have a higher pressure than is normally utilized for good GCIB transmission. This can result in additional evolution of monomers from gas cluster ions (beyond that resulting from the heating and/or excitement resulting from the initial gas cluster ionization event). Pressure may be arranged so that gas cluster ions have a short enough mean-free-path and a long enough flight path between ionizer and workpiece that they must undergo multiple collisions with background gas molecules. 
     For a homogeneous gas cluster ion containing N monomers and having a charge state of q and which has been accelerated through an electric field potential drop of V Acc  volts, the cluster will have an energy of approximately qV Acc /N I  eV per monomer, where N I  is the number of monomers in the cluster ion at the time of acceleration. Except for the smallest gas cluster ions, a collision of such an ion with a background gas monomer of the same gas as the cluster source gas will result in additional deposition of approximately qV Acc /N I  eV into the gas cluster ion. This energy is relatively small compared to the overall gas cluster ion energy (qV Acc ) and generally results in excitation or heating of the cluster and in subsequent evolution of monomers from the cluster. It is believed that such collisions of larger clusters with background gas seldom fragment the cluster but rather heats and/or excites it to result in evolution of monomers by evaporation or similar mechanisms. Regardless of the source of the excitation that results in the evolution of a monomer or monomers from a gas cluster ion, the evolved monomer(s) have approximately the same energy per particle, qV Acc /N I  eV, and retain approximately the same velocity and trajectory as the gas cluster ion from which they have evolved. When such monomer evolutions occur from a gas cluster ion, whether they result from excitation or heating due to the original ionization event, a collision, or radiant heating, the charge has a high probability of remaining with the larger residual gas cluster ion. Thus after a sequence of monomer evolutions, a large gas cluster ion may be reduced to a cloud of co-traveling monomers with perhaps a smaller residual gas cluster ion (or possibly several if fragmentation has also occurred). The co-traveling monomers following the original beam trajectory all have approximately the same velocity as that of the original gas cluster ion and each has energy of approximately qV Acc /N I  eV. For small gas cluster ions, the energy of collision with a background gas monomer is likely to completely and violently dissociate the small gas cluster and it is uncertain whether in such cases the resulting monomers continue to travel with the beam or are ejected from the beam. 
     Prior to the GCIB reaching the workpiece, the remaining charged particles (gas cluster ions, particularly small and intermediate size gas cluster ions and some charged monomers, but also including any remaining large gas cluster ions) in the beam are separated from the neutral portion of the beam, leaving only a Neutral Beam for processing the workpiece. 
     In typical operation, the fraction of power in the neutral beam components relative to that in the full (charged plus neutral) beam delivered at the processing target is in the range of from about 5% to 95%, so by the separation methods and apparatus of the present invention it is possible to deliver that portion of the kinetic energy of the full accelerated charged beam to the target as a Neutral Beam. 
     The dissociation of the gas cluster ions and thus the production of high neutral monomer beam energy is facilitated by 1) Operating at higher acceleration voltages. This increases qV Acc /N for any given cluster size. 2) Operating at high ionizer efficiency. This increases qV Acc /N for any given cluster size by increasing q and increases cluster-ion on cluster-ion collisions in the extraction region due to the differences in charge states between clusters; 3) Operating at a high ionizer, acceleration region, or beamline pressure or operating with a gas jet crossing the beam, or with a longer beam path, all of which increase the probability of background gas collisions for a gas cluster ion of any given size; 4) Operating with laser irradiation or thermal radiant heating of the beam, which directly promote evolution of monomers from the gas cluster ions; and 5) Operating at higher nozzle gas flow, which increases transport of gas, clustered and perhaps unclustered into the GCIB trajectory, which increases collisions resulting in greater evolution of monomers. 
     Measurement of the Neutral Beam cannot be made by current measurement as is convenient for gas cluster ion beams. A Neutral Beam power sensor is used to facilitate dosimetry when irradiating a workpiece with a Neutral Beam. The Neutral Beam sensor is a thermal sensor that intercepts the beam (or optionally a known sample of the beam). The rate of rise of temperature of the sensor is related to the energy flux resulting from energetic beam irradiation of the sensor. The thermal measurements must be made over a limited range of temperatures of the sensor to avoid errors due to thermal re-radiation of the energy incident on the sensor. For a GCIB process, the beam power (watts) is equal to the beam current (amps) times V Acc , the beam acceleration voltage. When a GCIB irradiates a workpiece for a period of time (seconds), the energy (joules) received by the workpiece is the product of the beam power and the irradiation time. The processing effect of such a beam when it processes an extended area is distributed over the area (for example, cm 2 ). For ion beams, it has been conveniently conventional to specify a processing dose in terms of irradiated ions/cm 2 , where the ions are either known or assumed to have at the time of acceleration an average charge state, q, and to have been accelerated through a potential difference of, V Acc  volts, so that each ion carries an energy of q V Acc  eV (an eV is approximately 1.6×10 −19  joule). Thus an ion beam dose for an average charge state, q, accelerated by V Acc  and specified in ions/cm 2  corresponds to a readily calculated energy dose expressible in joules/cm 2 . For an accelerated Neutral Beam derived from an accelerated GCIB as utilized in the present invention, the value of q at the time of acceleration and the value of V Acc  is the same for both of the (later-formed and separated) charged and uncharged fractions of the beam. The power in the two (neutral and charged) fractions of the GCIB divides proportionally to the mass in each beam fraction. Thus for the accelerated Neutral Beam as employed in the invention, when equal areas are irradiated for equal times, the energy dose (joules/cm 2 ) deposited by the Neutral Beam is necessarily less than the energy dose deposited by the full GCIB. By using a thermal sensor to measure the power in the full GCIB P G  and that in the Neutral Beam P N  (which is commonly found to be about 5% to 95% that of the full GCIB) it is possible to calculate a compensation factor for use in the Neutral Beam processing dosimetry. When P N  is aP G , then the compensation factor is, k=1/a. Thus if a workpiece is processed using a Neutral Beam derived from a GCIB, for a time duration is made to be k times greater than the processing duration for the full GCIB (including charged and neutral beam portions) required to achieve a dose of D ions/cm 2 , then the energy doses deposited in the workpiece by both the Neutral Beam and the full GCIB are the same (though the results may be different due to qualitative differences in the processing effects due to differences of particle sizes in the two beams.) As used herein, a Neutral Beam process dose compensated in this way is sometimes described as having an energy/cm′ equivalence of a dose of D ions/cm 2 . 
     Use of a Neutral Beam derived from a gas cluster ion beam in combination with a thermal power sensor for dosimetry in many cases has advantages compared with the use of the full gas cluster ion beam or an intercepted or diverted portion, which inevitably comprises a mixture of gas cluster ions and neutral gas clusters and/or neutral monomers, and which is conventionally measured for dosimetry purposes by using a beam current measurement. Some advantages are as follows: 
     1) The dosimetry can be more precise with the Neutral Beam using a thermal sensor for dosimetry because the total power of the beam is measured. With a GCIB employing the traditional beam current measurement for dosimetry, only the contribution of the ionized portion of the beam is measured and employed for dosimetry. Minute-to-minute and setup-to-setup changes to operating conditions of the GCIB apparatus may result in variations in the fraction of neutral monomers and neutral clusters in the GCIB. These variations can result in process variations that may be less controlled when the dosimetry is done by beam current measurement. 
     2) With a Neutral Beam, any material may be processed, including highly insulating materials and other materials that may be damaged by electrical charging effects, without the necessity of providing a source of target neutralizing electrons to prevent workpiece charging due to charge transported to the workpiece by an ionized beam. When employed with conventional GCIB, target neutralization to reduce charging is seldom perfect, and the neutralizing electron source itself often introduces problems such as workpiece heating, contamination from evaporation or sputtering in the electron source, etc. Since a Neutral Beam does not transport charge to the workpiece, such problems are reduced. 
     3) There is no necessity for an additional device such as a large aperture high strength magnet to separate energetic monomer ions from the Neutral Beam. In the case of conventional GCIB the risk of energetic monomer ions (and other small cluster ions) being transported to the workpiece, where they penetrate producing deep damage, is significant and an expensive magnetic filter is routinely required to separate such particles from the beam. In the case of the Neutral Beam apparatus of the invention, the separation of all ions from the beam to produce the Neutral Beam inherently removes all monomer ions. 
     One embodiment of the present invention provides a drug delivery system, comprising: a medical device having at least one surface region; and a drug layer formed on the at least one surface region, the drug layer comprised of a drug deposition on the at least one surface region and a carbonized or densified layer formed from the drug deposition by irradiation on an outer surface of the drug deposition, wherein the carbonized or densified layer does not penetrate through the drug deposition and is adapted to release drug from the drug deposition at a predetermined rate. 
     The at least one surface region may be a previously applied drug layer. The drug deposition may be encapsulated between the carbonized or densified layer and the at least one surface region. The drug deposition may not include any polymers. The medical device may be an implantable medical device. The irradiation may be gas-cluster ion beam irradiation. The irradiation may be Neutral Beam irradiation derived from a gas-cluster ion beam. The drug delivery system may further comprise at least one additional drug layer formed on the first said drug layer, the additional drug layer comprised of an additional drug deposition and an additional carbonized or densified layer formed from the additional drug deposition by irradiation on an outer surface of the additional drug deposition. 
     Another embodiment of the present invention provides a method of providing a drug delivery system, comprising the steps of: providing a medical device having at least one surface region; 
     depositing a drug layer on the at least one surface region; and forming a carbonized or densified layer on an outer surface of the drug layer by irradiating the outer surface of the drug layer, wherein the barrier layer does not penetrate the drug layer and is adapted to release drug from the drug layer at a predetermined rate. 
     The method may further comprise the steps of depositing at least one additional drug layer on the first said carbonized or densified layer and forming an additional carbonized or densified layer on an outer surface of the at least one additional drug layer by irradiating an outer surface of the at least one additional drug layer. The step of depositing may include using drug substances without any polymer material. The at least one surface region may be a previously applied drug layer. The step of forming may encapsulate the drug layer. The irradiating may make use of a gas-cluster ion beam. The irradiating may use a Neutral Beam derived from a gas-cluster ion beam. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       For a better understanding of the present invention, together with other and further objects thereof, reference is made to the accompanying drawings, wherein: 
         FIG. 1  is a schematic view of a gas cluster ion beam processing system used for practicing the method of the present invention; 
         FIG. 2  is an exploded view of a portion of the gas cluster ion beam processing system of  FIG. 1  showing the workpiece holder; 
         FIG. 3  is an atomic force microscope image showing the surface of a coronary stent before GCIB processing; 
         FIG. 4  is an atomic force microscope image showing the surface of a coronary stent after GCIB processing; 
         FIGS. 5A-5H  are illustrations of a surface region of a medical device at various stages of drug delivery system formation in accordance with an embodiment of the present invention; 
         FIGS. 6A-6C  are illustrations of alternative drug delivery structure embodiments in accordance with the present invention; 
         FIG. 7  is a cross section of a drug delivery system prior to processing in accordance with the present invention; 
         FIG. 8  is a cross section of the drug delivery system of  FIG. 5  shown during gas cluster ion beam processing performed in accordance with the present invention; 
         FIG. 9  is a schematic illustrating elements of a GCIB processing apparatus  1100  for processing a workpiece using a GCIB; 
         FIG. 10  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; 
         FIG. 11  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; 
         FIG. 12  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; 
         FIGS. 13A, 13B, 13C, and 13D  show processing results indicating that for a metal film, processing by a neutral component of a beam produces superior smoothing of the film compared to processing with either a full GCIB or a charged component of the beam; 
         FIGS. 14A and 14B  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; 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     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. 
     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. 
     Beams of energetic ions, electrically charged atoms or molecules accelerated through high voltages under vacuum, are widely utilized to form semiconductor device junctions, to smooth surfaces by sputtering, and to enhance the properties of semiconductor thin films. In the present invention, these same beams of energetic ions are utilized for affecting surface characteristics of drug eluting medical devices, such as, for example, coronary stents, thereby enhancing the drug delivery properties and the bio-compatibility of such drug delivery systems. 
     In the preferred embodiment of the present invention, gas cluster ion beam GCIB processing is utilized. Gas cluster ions are formed from large numbers of weakly bound atoms or molecules sharing common electrical charges and accelerated together through high voltages to have high total energies. Cluster ions disintegrate upon impact and the total energy of the cluster is shared among the constituent atoms. Because of this energy sharing, the atoms are individually much less energetic than the case of conventional ions or ions not clustered together and, as a result, the atoms penetrate to much shorter depths. Surface sputtering effects are orders of magnitude stronger than corresponding effects produced by conventional ions, thereby making important microscale surface effects possible that are not possible in any other way. 
     The concept of GCIB processing has only emerged over the past decade. Using a GCIB for dry etching, cleaning, and smoothing of materials is known in the art and has been described, for example, by Deguchi, et al. in U.S. Pat. No. 5,814,194, “Substrate Surface Treatment Method”, 1998. Because ionized clusters containing on the order of thousands of gas atoms or molecules may be formed and accelerated to modest energies on the order of a few thousands of electron volts, individual atoms or molecules in the clusters may each only have an average energy on the order of a few electron volts. It is known from the teachings of Yamada in, for example, U.S. Pat. No. 5,459,326, that such individual atoms are not energetic enough to significantly penetrate a surface to cause the residual sub-surface damage typically associated with plasma polishing. Nevertheless, the clusters themselves are sufficiently energetic (some thousands of electron volts) to effectively etch, smooth, or clean hard surfaces. 
     Because the energies of individual atoms within a gas cluster ion are very small, typically a few eV, the atoms penetrate through only a few atomic layers, at most, of a target surface during impact. This shallow penetration of the impacting atoms means all of the energy carried by the entire cluster ion is consequently dissipated in an extremely small volume in the top surface layer during a period on the order of 10 −12  seconds (i.e. one picosecond). This is different from the case of ion implantation which is normally done with conventional monomer ions and where the intent is to penetrate into the material, sometimes penetrating several thousand angstroms, to produce changes in the surface properties of the material. Because of the high total energy of the cluster ion and extremely small interaction volume, the deposited energy density at the impact site is far greater than in the case of bombardment by conventional monomer ions. 
     Reference is now made to  FIG. 1  of the drawings which shows the GCIB processor  100  of this invention utilized for applying or adhering drugs to the surface of a medical device such as, for example, coronary stent  10 . Although not limited to the specific components described herein, the processor  100  is made up of a vacuum vessel  102  which is divided into three communicating chambers, a source chamber  104 , an ionization/acceleration chamber  106 , and a processing chamber  108  which includes therein a uniquely designed workpiece holder  150  capable of positioning the medical device for uniform GCIB bombardment and drug application by a gas cluster ion beam. 
     During the processing method of this invention, the three chambers are evacuated to suitable operating pressures by vacuum pumping systems  146   a ,  146   b , and  146   c , respectively. A condensable source gas  112  (for example argon or N 2 ) stored in a cylinder  111  is admitted under pressure through gas metering valve  113  and gas feed tube  114  into stagnation chamber  116  and is ejected into the substantially lower pressure vacuum through a properly shaped nozzle  110 , resulting in a supersonic gas jet  118 . Cooling, which results from the expansion in the jet, causes a portion of the gas jet  118  to condense into clusters, each consisting of from several to several thousand weakly bound atoms or molecules. A gas skimmer aperture  120  partially separates the gas molecules that have not condensed into a cluster jet from the cluster jet so as to minimize pressure in the downstream regions where such higher pressures would be detrimental (e.g., ionizer  122 , high voltage electrodes  126 , and process chamber  108 ). Suitable condensable source gases  112  include, but are not necessarily limited to argon, nitrogen, carbon dioxide, oxygen. 
     After the supersonic gas jet  118  containing gas clusters has been formed, the clusters are ionized in an ionizer  122 . The ionizer  122  is typically an electron impact ionizer that produces thermo-electrons from one or more incandescent filaments  124  and accelerates and directs the electrons causing them to collide with the gas clusters in the gas jet  118 , where the jet passes through the ionizer  122 . The electron impact ejects electrons from the clusters, causing a portion the clusters to become positively ionized. A set of suitably biased high voltage electrodes  126  extracts the cluster ions from the ionizer  122 , forming a beam, then accelerates the cluster ions to a desired energy (typically from 1 keV to several tens of keV) and focuses them to form a GCIB  128  having an initial trajectory  154 . Filament power supply  136  provides voltage V F  to heat the ionizer filament  124 . Anode power supply  134  provides voltage V A  to accelerate thermoelectrons emitted from filament  124  to cause them to bombard the cluster containing gas jet  118  to produce ions. Extraction power supply  138  provides voltage V E  to bias a high voltage electrode to extract ions from the ionizing region of ionizer  122  and to form a GCIB  128 . Accelerator power supply  140  provides voltage V Acc  to bias a high voltage electrode with respect to the ionizer  122  so as to result in a total GCIB acceleration energy equal to V Acc  electron volts (eV). One or more lens power supplies ( 142  and  144 , for example) may be provided to bias high voltage electrodes with potentials (V L1  and V L2  for example) to focus the GCIB  128 . 
     A medical device, such as coronary stent  10 , to be processed by the GCIB processor  100  is held on a workpiece holder  150 , and disposed in the path of the GCIB  128  for irradiation. The present invention may be utilized with medical devices composed of a variety of materials, such as metal, ceramic, polymer, or combinations thereof. In order for the stent to be uniformly processed using GCIB, the workpiece holder  150  is designed in a manner set forth below to manipulate the stent  10  in a specific way. 
     Referring now to  FIG. 2  of the drawings, medical device surfaces that are non-planar, such as those of stents, must remain oriented within a specific angle tolerance with respect to the normal beam incidence to obtain paramount effect to the stent surfaces utilizing GCIB. This requires a fixture or workpiece holder  150  with the ability to be fully articulated to orient all non-planar surfaces of stent  10  to be modified within that specific angle tolerance at a constant exposure level for process optimization and uniformity. Any stent  10  containing surfaces that would be exposed to the process beam at angles of greater than +/−15 degrees from normal incidence may require manipulation. More specifically, when applying GCIB to a coronary stent  10 , the workpiece holder  150  is rotated and articulated by a mechanism  152  located at the end of the GCIB processor  100 . The articulation/rotation mechanism  152  preferably permits 360 degrees of device rotation about longitudinal axis  154  and sufficient device articulation about an axis  156  perpendicular to axis  154  to maintain the stent&#39;s surface to within +/−15 degrees from normal beam incidence. 
     Referring back to  FIG. 1 , under certain conditions, depending upon the size of the coronary stent  10 , a scanning system may be desirable to produce uniform smoothness. Although not necessary for GCIB processing, two pairs of orthogonally oriented electrostatic scan plates  130  and  132  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  156  provides X-axis and Y-axis scanning signal voltages to the pairs of scan plates  130  and  132  through lead pairs  158  and  160  respectively. The scanning signal voltages are commonly triangular waves of different frequencies that cause the GCIB  128  to be converted into a scanned GCIB  148 , which scans the entire surface of the stent  10 . Additional means for orienting, articulating and/or rotating devices such as stents and orthopedic products are disclosed in U.S. Pat. No. 6,491,800 to Kirkpatrick, et al., U.S. Pat. No. 6,676,989 to Kirkpatrick, et al., and U.S. Pat. No. 6,863,786 to Blinn, et al., the contents of each which are hereby incorporated by reference. 
     When beam scanning over an extended region is not desired, processing is generally confined to a region that is defined by the diameter of the beam. The diameter of the beam at the stent&#39;s surface can be set by selecting the voltages (V L1  and/or V L2 ) of one or more lens power supplies ( 142  and  144  shown for example) to provide the desired beam diameter at the workpiece. 
     In one processing step related to the present invention, the surface of a medical device is irradiated with a GCIB prior to the deposition of any substance on the surface thereof. This will remove any contaminants and oxide layers from the stent surface rendering the surface electrically active and capable of attracting and bonding drug and polymer molecules that are then introduced to the surface. 
     As the atomic force microscope (AFM) images shown in  FIGS. 3 and 4  demonstrate, it is possible to dramatically affect the medical device surface utilizing gas cluster ion beam processing.  FIG. 3  shows a stent surface before GCIB treatment with gross surface micro-roughness on a strut edge. The surface roughness measured an R a  of 113 angstroms and an R RMS  of 148 angstroms. These irregularities highlight the surface condition at the cellular level where thrombosis begins.  FIG. 4  shows the stent surface after GCIB processing where the surface micro-roughness has been eliminated without any measurable physical or structural change to the integrity of the stent itself. The post-GCIB surface roughness measured an R a  of 19 angstroms and an R RMS  of 25 angstroms. In this manner, GCIB processing also provides the added benefit of smoothing the surface of the medical device. Non-smooth surfaces may snare fibrinogen, platelets, and other matter further promoting stenosis. 
     With reference to  FIGS. 5A-5F , a method of producing a drug delivery system will now be described.  FIG. 5A  illustrates a surface region  12  of a medical device such as, for example, stent  10 , that has been positioned in a vacuum chamber such that it can be irradiated with gas clusters  15  of a GCIB, as would occur in an optional smoothing process step.  FIG. 6A  illustrates an exemplary drug delivery structure in accordance with an embodiment of the present invention. Note that the drug delivery structure may cover all or less than the entirety of the exterior surface of stent  10 . In the latter case, surface region  12  represents but one of a plurality of spatially distinct surface regions  12 - 14  of stent  10  upon which the drug delivery system is formed. Each of the distinct surface regions  12 - 14  may elute the same or similar type of drug, or completely distinct types of drugs. For ease in understanding, the description that follows focuses on the formation of the drug delivery structure at surface region  12  only. 
       FIG. 5B  illustrates surface region  12  as being relatively smooth, following an optional surface preparation step through GCIB irradiation. As described above, such processing removes contaminants and electrically activates the surface region  12 .  FIG. 5C  shows a drug layer  16 , which may be deposited by any of the techniques described above, and which preferably has been deposited to have a substantially uniform thickness in the vicinity of region  12 . A “deposited drug layer” is used herein to refer to a contiguous drug layer deposited over the entirety of the surface of the medical device, such as deposited drug layer  16 , or alternatively may be used in a collective sense to refer to numerous spatially distinct deposits of the same or different therapeutic agents on the surface  12 . In either case, the deposited drug layer is GCIB irradiated to form an adhered drug layer on the device surface from which a portion of the deposited agent will be released over time to a patient&#39;s tissue adjacent the medical device. 
       FIG. 5D  illustrates the step of irradiating the first deposited drug layer  16  with GCIB gas clusters  17 . This results in the formation of a first adhered drug layer  18 , which is comprised of two primary components, such as shown in  FIG. 5E . First adhered drug layer  18 , and subsequently formed adhered drug layers, each include a carbonized drug matrix  20  having a plurality of interstices  22  in which will be disposed the remainder of the deposited drug that was not carbonized by the GCIB. Drug layer  18  is adhered to the surface region  12 , and a portion of the non-carbonized drug will be released at an expected rate (characterized as an elution profile) from the adhered drug layer  18  by diffusion through the interstices  22  of the carbonized drug matrix  20 . A number of the interstices  22  are interconnected, and a portion of the interstices are open at each surface of the drug matrix  20  so as to permit non-carbonized drug to eventually elute from a substantial number of the interstices  22  of the drug matrix  20 . 
       FIGS. 5F-5H  illustrate how the drug deposition and GCIB irradiation process steps may be repeated, generally, to achieve multi-layered drug delivery structures having variable and extremely accurate drug loading. More particularly,  FIG. 5F  illustrates a second drug layer  24  deposited upon the first adhered drug layer  18  using the same or an alternative deposition process. The second drug layer  24  is then irradiated ( FIG. 5G ) with GCIB gas clusters  26  delivering substantially similar dosing or different, depending upon desired elution profile. Similar GCIB irradiation doses delivered to substantially similar or identical therapeutic agents will result in substantially similar elution profiles between or among adhered layers.  FIG. 5H  illustrates a drug delivery system comprised of an adhered drug layer  28  that is further comprised of the first adhered drug layer  18  and a second adhered drug layer  30 . As many repetitions of the drug deposition and GCIB irradiation steps as needed to attain an overall elution profile, or profiles (if multiple therapeutic agents are utilized), may be performed. In one preferred embodiment, the first adhered drug layer  18  and second adhered drug layer  30  are similarly formed to have similar elution profiles, such that, as drug is released from the interstices  32  of layer  30 , drug eluting from layer  18  into layer  30  replenishes the released drug. The adhered drug layers  18 ,  30  are not necessarily, however, comprised of the same drug substance(s). 
     Several alternative drug delivery systems in accordance with the present invention will now be described, with reference to  FIGS. 6A-6C . 
     As noted above, multiple factors, including the thickness of the deposited drug layer, will determine whether GCIB gas clusters will penetrate a deposited drug layer so as to reach the surface onto which a new drug layer is to be adhered.  FIG. 6A  illustrates a drug delivery system  38  (similar to that illustrated in  FIG. 5E ) that is further comprised of spatially distinct adhered drug structures  34 - 36  formed when GCIB gas clusters penetrate a thinly deposited drug layer (e.g., on the order of several to tens of Angstroms, or greater.) Note that some portion of the adhered drug structures  34 - 36  are bonded (or stitched) to associated, spatially distinct surface regions  12 - 14 . Formation of each of the adhered drug structures  34 - 36  may be accomplished nearly simultaneously or in separate processing routines. The therapeutic agent to be released from each of the adhered drug structures  34 - 36  is deposited at the associated spatially distinct surface region  12 - 14  and then GCIB irradiated. Again, the drug deposited at each surface region  12 - 14  is not necessarily the same. Forming adhered drug structures on less than the entire surface of the medical device has the benefit of cost savings when an expensive drug is to be used. Also, certain drugs may only need to be delivered at particular locations, such as at a site of significant tissue interaction with an implanted medical device. 
       FIG. 6B  illustrates an alternative embodiment of a drug delivery system, such as may be formed when the GCIB does not penetrate the thickness of a drug layer deposited on the surface region  12  of the medical device  10 . In such embodiments, a carbonized drug matrix  40  is still formed having interstices within which some portion of non-carbonized drug is disposed, and from which non-carbonized drug is released, however the drug matrix  40  does not extend to the surface  12  of the medical device  10 . Rather, the carbonized matrix  40  encapsulates the remainder of first deposited drug  16  that was not carbonized by the GCIB (and not captured in the interstices), between the drug matrix  40  and the surface  12  of the device  10 . As noted above, the expression “adhered drug layer” as used herein refers collectively to the carbonized matrix  40 , and the non-carbonized portions of the deposited drug, whether disposed in the interstices or encapsulated by the drug matrix  40  and the device surface. 
       FIG. 6C  illustrates an alternative embodiment of a drug delivery system, such as may be formed when a second layer of deposited drug is deposited on an underlying carbonized matrix of a previously deposited and irradiated layer, as for example adding a second drug layer to the drug delivery system of  FIG. 6B . A second drug layer is deposited over the carbonized drug matrix  40  of the previous layer. The second drug layer is irradiated by GCIB. The GCIB does not penetrate the thickness of the drug layer second deposited on the carbonized drug matrix  40 . In such embodiments, a second carbonized drug matrix  42  is formed having interstices within which some portion of non-carbonized drug is disposed, and from which non-carbonized drug is released, however the second carbonized drug matrix  42  does not extend to the surface of the first carbonized drug matrix  40  on the medical device  10 . Rather, the carbonized matrix  42  encapsulates the remainder of second deposited drug  24  that was not carbonized by the GCIB (and not captured in the interstices), between the drug matrix  42  and the surface of the first carbonized drug matrix  40  of the device  10 . The therapeutic agent to be released from each of the adhered non-carbonized drug layers  16  and  24  are not necessarily the same. 
     As a further alternative to the above different examples, different types of GCIB derived irradiation may be used on different drug layers in the same device to achieve a desired drug elution effect. 
     With reference to  FIG. 7 , a drug delivery system  50 , which includes a drug containing medium  52  and an optional substrate or medical device  54 , is shown prior to processing by the method of the present invention. Medical device  54  is only representational and may take any suitable form. Device  54  may include an implantable medical device such as a stent or any other medical device which may benefit from an in situ drug delivery mechanism. Optionally, the use of substrate or device  54  may be limited to the fabrication of drug containing medium  52 , wherein substrate or device  54  is removed from medium  52  prior to implantation. Substrate or device  54  maybe he constructed of any suitable material such as, for example, metal, ceramic or a polymer. Portions of substrate or device  54  may also be surface treated using GCIB in accordance with the method mentioned above, prior to the application of drug/polymer medium  52 . 
     Drug containing medium  52  may take any suitable form such as the various polymer arrangements discussed above. Medium  52  may include just a single layer of drug containing material, or it may include multiple layers  56 ,  58 ,  60 , as described above. Although the existing art identifies the use of an outer layer to control initial drug release, the process of the present invention may be used with this known arrangement to further control surface characteristics of the medium, including the drug release rate after initial in situ liquid exposure. Drug medium  52  may be applied to device  54  in any suitable arrangement from just a portion to complete or almost complete enclosure of device  54 . 
     One method of application of medium  52  to device  54  uses a drug polymer mixture with a volatile solvent, which is deposited upon a surface of device  54 . The solvent is evaporated to leave a cohesive drug/polymer mixture in the form of medium  52 , attached to the substrate. Once the solvent is evaporated, drug medium  52  may form a cohesive mixture or mass and thereby provide a suitable drug delivery system, even in the absence of device  54 . 
     With reference to  FIG. 8 , the drug delivery system  50  is shown undergoing irradiation with a gas cluster ion beam. A stream  70  of gas cluster molecules is being scanned across the cross section of drug delivery device  50 . The clusters  72  break up upon impact with the surface  74  resulting in the shallow implantation of individual or small groups of molecules  76 . Most of the individual molecules  76  stop within the first couple of molecular levels of medium  52  with the result that most of a thin layer  78  at surface  74  is densified or carbonized by the impinging molecules. The sealing of surface  74  is not complete, as various openings  79  remain in surface  74  which openings allow for the elution of drugs from medium  52 . Thus, it is through the amount of GCIB irradiation that the characteristics of surface  74  are determined. The greater the amount of irradiation, the fewer and smaller are the openings in surface  74 , thereby slowing the release of drugs from medium  52 . Also, this densification or carbonization of surface  74  causes pacification or sealing of surface  74 , which can decrease the bio-reactivity of surface  74  in contact with living tissue. In the case of some polymer materials which may be used for medium  52 , the densification or carbonization can limit the release of volatile organic compounds by the medium  52  into surrounding living tissue. Thus, the process of the present invention enhances the choices of materials which may be used to construct medium  52  and can reduce risk factors associated with those material choices. 
     An Accelerated Low Energy Neutral Beam Derived from an Accelerated GCIB 
     Reference is now made to  FIG. 9 , 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  1146   a ,  1146   b , and  1146   c , 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 f  to heat the ionizer filament  1124 . Anode power supply  1134  provides anode voltage V 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 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 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 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 . 
     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. 
       FIG. 10  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. 
     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 fully 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. 
     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. 
       FIG. 11  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  1146   b  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 beamline 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  1146   b . 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  1146   b , the pressure in the beamline chamber  1107  equilibrates at a pressure, P 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 B  may be approximately 6×10 −5  torr (8×10 −3  pascal). Thus the product of pressure and beam path length is approximately 6×10 −3  torr-cm (0.8 pascal-cm) and the gas target thickness for the beam is approximately 1.94×10 14  gas molecules per cm 2 , which is observed to be effective for dissociating the gas cluster ions in the GCIB  1128 . V 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 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 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 D  flows through electrical lead  1312  and current sensor/display  1310  for indication. When V D  is zero, the GCIB  1128  is undeflected and travels to the workpiece  1160  and the workpiece holder  1162 . The GCIB beam current I 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 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 D  is set to zero, the beam current, I 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 B . V D  is increased until all measured beam current is transferred from I B  to I D  and I D  no longer increases with increasing V 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 B . Following such a calibration process, additional workpieces may be processed using the calibrated exposure duration. 
     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. 
       FIG. 12  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 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 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 D  is 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 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 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 D  to deflection plate  1302  until all of the current I 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 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 D , and determines a current ratio between the initial values of I B  and I D . During processing, the instantaneous I D  measurement multiplied by the initial I B /I D  ratio may be used as a proxy for continuous measurement of the I 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 D  for correction of any beam fluctuation during the process. 
       FIGS. 13A through 13D  show the comparative effects of full and charge separated beams on a gold thin film. In an experimental setup, a gold film deposited on a silicon substrate was processed by a full GCIB (charged and neutral components), a Neutral Beam (charged components deflected out of the beam), and a deflected beam comprising only charged components. All three conditions are derived from the same initial GCIB, a 30 kV accelerated Ar GCIB. Gas target thickness for the beam path after acceleration was approximately 2×10 14  argon gas atoms per cm 2 . For each of the three beams, exposures were matched to the total energy carried by the full beam (charged plus neutral) at an ion dose of 2×10 15  gas cluster ions per cm 2 . Energy flux rates of each beam were measured using a thermal sensor and process durations were adjusted to ensure that each sample received the same total thermal energy dose equivalent to that of the full (charged plus neutral) GCIB dose. 
       FIG. 13A  shows an atomic force microscope (AFM) 5 micron by 5 micron scan and statistical analysis of an as-deposited gold film sample that had an average roughness, Ra, of approximately 2.22 nm.  FIG. 13B  shows an AFM scan of the gold surface processed with the full GCIB—average roughness, Ra, has been reduced to approximately 1.76 nm.  FIG. 13C  shows an AFM scan of the surface processed using only charged components of the beam (after deflection from the neutral beam components)—average roughness, Ra, has been increased to approximately 3.51 nm.  FIG. 13D  shows an AFM scan of the surface processed using only the neutral component of the beam (after charged components were deflected out of the neutral beam components)—average roughness, Ra, is smoothed to approximately 1.56 nm. The full GCIB processed sample (B) is smoother than the as deposited film (A). The Neutral Beam processed sample (D) is smoother than the full GCIB processed sample (B). The sample (C) processed with the charged component of the beam is substantially rougher than the as-deposited film. The results support the conclusion that the neutral portions of the beam contribute to smoothing and the charged components of the beam contribute to roughening. 
       FIGS. 14A and 14B  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. 14A  represents a sample irradiated using an argon GCIB (including the charged and neutral components) accelerated using V Acc  of 30 kV with an irradiated dose of 2×10 15  gas cluster ions per cm 2 .  FIG. 14B  represents a sample irradiated using a Neutral Beam derived from an argon GCIB accelerated using V Acc  of 30 kV. The Neutral Beam was irradiated with a thermal energy dose equivalent to that of a 30 kV accelerated, 2×10 15  gas cluster ion per cm 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. 14A  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. 14B  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. 14A  exhibits damage and etching caused by the full beam where it passed through the mask. The sample shown in  FIG. 14B  exhibits no visible effect. In elution rate tests in physiological saline solution, the samples processed like the  FIG. 14B  sample (but without mask) exhibited superior (delayed) elution rate compared to the samples processed like the  FIG. 14A  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. 
     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 results 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 plus 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 Group—no irradiation was performed; Group 1—irradiated with a Neutral Beam derived from a GCIB accelerated with a V Acc  of 30 kV. The Group 1 irradiated beam energy dose was equivalent to that of a 30 kV accelerated, 5×10 14  gas cluster ion per cm 2  dose (energy equivalence determined by beam thermal energy flux sensor); Group 2—irradiated with a Neutral Beam derived from a GCIB accelerated with a V Acc  of 30 kV. The Group 2 irradiated beam energy dose was equivalent to that of a 30 kV accelerated, 1×10 14  gas cluster ion per cm 2  dose (energy equivalence determined by beam thermal energy flux sensor); and Group 3—irradiated with a Neutral Beam derived from a GCIB accelerated with a V Acc  of 25 kV. The Group 3 irradiated beam energy dose was equivalent to that of a 25 kV accelerated, 5×10 14  gas cluster ion per cm 2  dose (energy equivalence determined by beam thermal energy flux sensor). 
     
       
         
           
               
               
             
               
                   
                 TABLE 1 
               
             
            
               
                   
                   
               
               
                   
                 Group 
               
               
                   
                 [Dose] 
               
               
                   
                 {V Acc } 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Group 1 
                 Group 2 
                 Group 3 
               
               
                   
                   
                 [5 × 10 14 ] 
                 [1 × 10 14 ] 
                 [5 × 10 14 ] 
               
               
                   
                 Control 
                 {30 kV} 
                 {30 kV} 
                 {25 kV} 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Start 
                 Elution 
                   
                 Start 
                 Elution 
                   
                 Start 
                 Elution 
                   
                 Start 
                 Elution 
                   
               
               
                   
                 Load 
                 Loss 
                 Elution 
                 Load 
                 Loss 
                 Elution 
                 Load 
                 Loss 
                   
                 Load 
                 Loss 
                 Elution 
               
               
                 Coupon # 
                 (μg) 
                 (μg) 
                 Loss % 
                 (μg) 
                 (μg) 
                 Loss % 
                 (μg) 
                 (μg) 
                 Loss % 
                 (μg) 
                 (μg) 
                 Loss % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 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 
               
               
                 σ 
                 5 
                 7 
                   
                 9 
                 3 
                   
                 9 
                 13 
                   
                 5 
                 2 
               
            
           
           
               
               
               
               
               
            
               
                 p 
                   
                 0.00048 
                 0.014 
                 0.00003 
               
               
                 value 
               
               
                   
               
            
           
         
       
     
     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. 
     Studies have suggested that a wide variety of drugs may be useful at the site of contact between the medical device and the in situ environment. For example, drugs such as anti-coagulants, anti-prolifics, antibiotics, immune-suppressing agents, vasodilators, anti-thrombotic substances, anti-platelet substances, and cholesterol reducing agents may reduce instances of restenosis when diffused into the blood vessel wall after insertion of the stent. Although the present invention is described in reference to stents, its applications and the claims hereof are not limited to stents and may include any contact with a living body where drug delivery may be helpful. 
     Although the benefits of employing the Neutral Beam for electrical charging-free processing have been described with respect to various electrically insulating and/or high electrical resistivity materials such as insulating drug coatings, polymers, and other materials, it is understood by the inventors that all materials of poor or low electrical conductivity may benefit from using the Neutral Beam of the invention as a substitute for processing using techniques that transfer charges, like ion beams (including GCIB), plasmas, etc. It is intended that the scope of the invention includes all such materials. It is further understood by the inventors that Neutral Beam processing is often advantageous as compared to GCIB and other ion beams, beyond the advantage of reduced surface charging. Thus it is also valuable for processing even materials that are electrically conductive (such as, for example, metal stents or other metal medical devices or components), due to other the advantages of Neutral Beam processing, especially of neutral monomer beam processing, which produces less surface damage, better smoothing, and smoother interfaces between processed and underlying unprocessed regions, even in metals and highly conductive materials. It is intended that the scope of the invention include processing of such materials. 
     Although the benefits of employing Neutral Beam for modifying the surfaces of drug materials on medical devices to control an elution rate of a drug in a fluid environment have been disclosed as an example, it is understood by the inventors that surfaces of other organic or even some inorganic materials on other types of substrates may be modified to change the rate at which they elute or release material in a fluid environment, or evaporate or sublimate or release material in an air or other gaseous environment or in a vacuum. It is intended that the scope of the invention include processing of such materials using accelerated Neutral Beams derived from accelerated GCIBs. Such materials may be in the form of a coating on a substrate or in a bulk material form. 
     Although the invention has been described with respect to various embodiments, it should be realized this invention is also capable of a wide variety of further and other embodiments within the spirit and scope of the invention.