WO2023278386A1

WO2023278386A1 - Protection of orthopedic implants from wear

Info

Publication number: WO2023278386A1
Application number: PCT/US2022/035233
Authority: WO
Inventors: Thomas Webster; Stephen M. Blinn; Joseph Khoury; Bruce Garcia; William MCLENDON; Sean R. Kirkpatrick
Original assignee: Exogenesis Corporation
Priority date: 2021-06-28
Filing date: 2022-06-28
Publication date: 2023-01-05

Abstract

Orthopedic implants are treated by Neutral Beam irradiation to achieve on at least one or more portions of the implant surface energies matching surface energies of lubricious proteins of the implant usage environment. The irradiation reduces rubbing of the implant and debris shedding from the implant in a mammalian joint region.

Description

PROTECTION OF ORTHOPEDIC IMPLANTS FROM WEAR

Cross Reference to Related Applications

This application claims the priority of U.S. Provisional Patent Application No. 63/215,718 entitled Protection of Orthopedic Implants from Wear which was filed on June 28, 2021, the contents of which are incorporated herein in their entirety.

Background

The demand for orthopedic implants has increased significantly in concert with the rise in the world geriatric population and accompanying osteoporosis and osteoarthritis. More orthopedic implants are being placed into a wider population of patients with diverse and challenging immune systems. With that, concerns are growing for implant failure from infection, excessive prolonged chronic inflammation, and wear debris as articulating surfaces potentially causing bone osteolysis and implant loosening.

Ultra high molecular weight polyethylene (UHMWPE) has been the coating of choice for articulating surfaces of artificial joints to reduce wear-related orthopedic implant failure. However, UHMWPE can still wear as it produces wear particles detrimental to establishing and maintaining juxtaposed bone growth. UHMWPE wear ranges from 0.01 to 0.56 mm per year (averaging about 0.29 mm), decreasing with time to 0.15 mm per year after 9 years. Such wear particles reside at the interface between bone and the implant causing bone cell death, osteoclast mediated bone resorption, and possibly implant loosening. While there have been advances to improve the wear properties of polyethylene chemistry (such as the addition of cross-linking agents) UHMWPE wear remains a persistent problem in orthopedics.

UHMWPE wear debris can also contribute to implant infection, which is a growing healthcare problem. The traditional manner to treat orthopedic implant infection has been through a combination of surgical debridement and antibiotics. However, the overuse and misuse of antibiotics trigger genetic modification in bacteria and antimicrobial resistance (AMR), one of the most disturbing societal health concerns. Indeed, the US Centers for Disease Control and Prevention (CDC) rank 14 bacterial strains as urgent or serious threats to infection, as there are few available antibiotics to treat their drug-resistant phenotypes. For instance, Staphylococcus aureus has developed resistance to beta-lactam antibiotics, such as methicillin, leading to the appearance of Methicillin-resistant Staphylococcus aureus (MRS A), one of the most proliferative killers in the healthcare system.

Once an infection has occurred, eradicating it from the implant or the bone may be impossible with antibiotics or even with a combination of antibiotics and surgery, because of the relatively poor blood supply and unique environment of bone and the prosthetic interface. Many bacteria form a protective biofilm that shields them from exposure to systemic antibiotics or antibiotic irrigants requiring surgical debridement of prosthetic joint infection (PJI). Such interventions often lead to removal of well-fixed implants with excess morbidity from fractures, bone loss and muscle/tissue damage. Even with implant removal, some infections can be impossible to eradicate, and recurrence remains a significant issue. Prevention through development and use of implants that reduce bacteria colonization in the first place is then critical.

Summary

According to aspects of the present disclosure, modifying the surface of UHMWPE to increase the adsorption of endogenous lubricating proteins (such as lubricin) and endogenous antibacterial proteins (such as mucin, casein, and lubricin) could improve UHMWPE wear and reduce bacterial infections. There has been extensive research showing that polymeric materials which possess nanoscale surface properties alter surface energy to attract the adsorption of such proteins to reduce bacteria colonization without resorting to antibiotic use.

Aspects of the present disclosure provide a technique for treating implants against certain modes of wear and consequent inflammation, shedding debris and infection. The disclosed implant treatment includes irradiation of the implant surface or one or more portions thereof by a high energy Neutral Beam (Accelerated Neutral Atom Beam or like radiation) to effect nano scale surface modification of the UHMWPE implant surface to a 20-50 nanometer typography leading to enhanced wettability and surface energy reducing wear and also reducing bacterial attachment.

An object of the present disclosure modifies the surface of a common implantable EIHMWPE with ANAB, characterizes its surface and wear properties, and determines a wide range of in vitro bacteria functions on such surfaces without using antibiotics

Brief Description of the Drawings

Figures 1 A - 1C show AFM Characterization of the Unmodified and ANAB Modified UHMWPE according to an aspect of the present disclosure;

Figure 2 is a graph showing examples of bacteria colonization on the unmodified and ANAB modified Polyethlyene according to an aspect of the present disclosure.

Detailed Description

Embodiments of the present disclosure are applicable to ultra-high molecular weight polyethylene (UHMWPE) a material and like materials usable in making orthopedic implants (e.g. knee or ankle joints) and other configurations subject to rubbing abrasion when insufficiently protected by protective synovial fluid or cartilage, leading to consequent complications of shedding of debris the CHMWPE material, limiting bone growth of adjacent bone parts, bone cell death, bone resumption injection and possible joint loosening. This is exemplified, but not limited to, EIHMWPE knee articulation implant components rubbing against or impacting adjacent bone or other implant components of the joint.

According to aspects of the present disclosure, avoidance of such complications can be avoided by treating the implant pre-installation in a human or other mammal subject by a surface modification at nano-scale to establish a surface energy, of all or portion of the implant, equal or nearly so to the surface energy of lubricious substances such as e.g. proteins such as endogeneous inherently present as endogeneous (synovial) fluid content of the joint region or introduced to the region. The matching can prevent or mitigate the rubbing that leads to debris shedding from the implant and consequent complications stated above.

Accelerated Neutral Atom Beam (ANAB) technology is an accelerated particle beam process gaining acceptance as a tool for fast and economical nano-scale surface modification of implantable medical devices. ANAB bombard a material’ s surface by the high acceleration of neutral argon (Ar) atoms under vacuum . Upon impact with the surface, each atom’s high velocity causes it to penetrate ~ 2-3nm into the surface and its kinetic energy is converted into thermal energy. Although the total energy delivered to the surface is extremely low, the energy of each Ar atom, relative to its nanometer area of impact, is extremely high. The result is a thermal spike of picoseconds that ablates organic material within a relatively wide radius of each atom’s impact zone, creating a 20-50nm nanotopography superimposed on the existing microtopography. This is a subtractive technology that results in modifications of surface topography, wettability, and surface energy. These modifications are understood to be important in cell- surface interactions on implantable medical devices as they change initial protein interactions for which cells rely on to adhere. Controlling surface properties of biomaterials is vital in improving wear properties and reducing bacterial attachment.

As shown U.S. 2015/0351892 by Exogenesis Corporation, the ANAB or ANAB-like Neutral Beam can comprise a collimated high speed array of atoms, typically argon (Ar) or other inert gas imparting a target implant surface, portion with about a 2 x e¹⁶ Ar atoms per cm² with controlled dosimentary of atom beam speed, array density and duration of irradiation, in static or streaming modes. In ANAB form, the Neutral Beam is derived from an accelerated gas-cluster ion beam (GCIB) treated to separate charged cluster ions or stray single ions from the accelerated beams, with dosage monitoring and control. Reactive gas atoms or molecules atoms can be added as a minority portion of the neutral gas atoms for special case purposes.

Roughness studies of UHMWPE coupons, including irradiated forms and untreated control forms, showed doubling increases of average surface roughness (Ra), average of height (Rz), mean square surface roughness (Rq) and average peak-to-valley roughness (Rpn) compared to their original unmodified (control) forms, could absorb twice as much of lubricant mucin and casein compared to the controls as shown in Table 2 of the appended Webster, et al. article and in pin-on-disk wear studies of weight loss, had zero loss compared to 5.2 +/-1.1% for the control (Table 3) and highly reduced bacterial colonization (Figure 2 of the article) in assays of the coupons challengedby MDR-E.coli, E-coli, MRSA, Staph aureus (A); Pseudomonas aeruginosa and Staph epidermidis (SE).

The Neutral Beam approach to surface modification is a substractive technology in contrast to additive (e.g. coating) technology, involves no introduction of foreign solid or liquid substances to the implant or its usage environment. It avoids the need for antibiotics customarily used in prior art to inhibit or regress bacterial colonization. It also affords a stable implant surface for less vulnerable surface fractures or ablation than prior art implants of UHMWPE or other plastic, metallic or ceramic materials.

Examples

Materials

UHMWPE samples (from Regal Plastics of Irving, Texas, USA) were modified by ANAB with argon (Ar) gas on an accelerated particle beam system (nAccel 100 system by Vallum Corporation of Nashua, New Hampshire, USA.) with a deflector to remove charged clusters. Ar gas was flowed at 200 SCCM through a 100 mm diameter nozzle to create weakly bonded clusters consisting of Ar atoms. These clusters were then electron ionized resulting in a charged cluster which is then accelerated by introducing it to a 30-kV electrostatic field. Once accelerated, the cluster was then immediately broken apart by orchestrating its collisions with residual Ar gas atoms present along the beam path in the acceleration chamber. These collisions break the weak van der Waals bonds thus releasing individual neutral atoms along with smaller, charged clusters. The remaining charged clusters were then pushed away with an electrostatic deflector allowing the neutral atoms to maintain their initial momentum until they collide with the material surface. In this study, the effective dose of the ANAB was either 1.7el6 or 2.5el6 Ar atoms per cm². Samples were sterilized by UV light exposure before further use as described below.

Material Characterization Samples were characterized for surface roughness using standard AFM procedures. AFM measurements were taken using a Park Systems XE-70 instrument in non-contact mode. Silicon tips with a resonant frequency of -330 kHz and a force constant of 42 N/m were used (PointProbe® Plus, by Nanosensors of Neuchatel, Switzerland).

Further, the surface energy of the samples of interest was determined using standard contact angle measurements. For this, each sample was placed into 12-well plates. The well plates containing the samples were subsequently transferred to a clean room equipped with a Phoenix 150 Contact Angle Analyzer. A three-solvent system, i.e., deionized water, ethylene glycol, and glycerol, was adopted for evaluating the surface energies of the samples. Specifically, a 16 m\ drop per solvent was dropped onto the sample surfaces in triplicate for each of the sample identities, and images were obtained after 2 s. Contact angles and the surface energy of each substrate was determined by applying the Owens/ Wendt theory in tandem with contact angle data and solvent surface tension values, of which the latter were obtained from the literature. The Owens/W endt model structurally follows the mathematical formulation shown in Equation 1 below, where s and <T^/J _L are the dispersive and polar components respectively, of the the wetting liquid’s surface tension, where a^Ds and s^r s are the dispersive and polar components respectively, of the substrate’s surface energy, and where Q is the contact angle that the solvent makes with the substrate surface. The goal was to use ANAB to modify the UHMWPE surface until a surface energy close to the surface energy of endogenous proteins known to lubricate surfaces (lubricin) and reduce bacteria colonization (mucin, casein, and lubricin) was achieved.

theory

Wear Studies

To determine the wear properties of the ANAB modified to non-modified UHMWPE, we used the standard pin-on-disk method. For this test, the pin was Ti6A14V (by Alfa Aesar - Thermo Fisher Scientific of Heysham, Lancashire, UK)

United Kingdom) to mimic the hip stem and the disk was the unmodified and modified UHMWPE samples. The pin-on-disk portion of the system was submerged in a lubricin containing solution (100 micrograms/ml lubricin supplemented to DMEM+10% FBS) and was tested at 1500 rpm for 6 hours at room temperature. Wear was determined by measuring the weight of the samples before and after the wear tests.

Antibacterial Assays

This study determined in vitro bacteria colonization on the samples of interest to the present study. For this, the samples were separately seeded (106 CFU/ml) with bacteria (multi-drug resistant E. coli (ATCC 47107), E. coli (ATCC 25922), MRSA (ATCC 4330), Staph aureus (ATCC 33594), Pseudomonas aeruginosa (ATCC 39327), and Staph epidermidis (ATCC 14990)) as described below and were cultured for 24 hours. At that time, CFTi analysis was conducted. For each experiment, a single colony from the inoculation plate was used. A small amount of bacteria was taken from the stock culture, streaked onto an agar plate, and then used as the stock plate for further experiments. A single colony was picked from the TSB agar-plate, added to 5 mL of the media specified above and incubated at 37°C in humidified conditions under a 5% carbon dioxide atmosphere for 16 hours. Samples were then placed in a 24 well non-tissue culture plate followed by a cleaning procedure. 106 CFU/mL of each bacteria were then separately exposed to the material surfaces and incubated for 24 hours in DMEM supplemented with 10% fetal bovine serum. The bacteria solution was removed and the samples were rinsed twice with PBS while pipetting. Following this, the samples were transferred into 5 mL of PBS and sonicated for 5 min. Then, samples were transferred to 5 mL of fresh PBS buffer and sonicated for an additional 10 minutes. 10 mL of the bacterial suspension was then diluted to create subsequent dilutions (10-3 and 10-4). Following this, 0.1 mL of each of the 10-3 and 10-4 dilutions were plated and the number of bacterial colonies formed on each sample counted and using these values, the number of bacteria/mL determined.

Statistical Analysis

All experiments were run in triplicate and repeated a minimum of three times per substrate type. Numerical data were analyzed using Analysis of Variance (ANOVA); values of p < 0.05 were considered significant. Duncan’s multiple range tests were used to determine differences between means. Results

Surface Characterization

As expected, the UHMWPE samples treated with ANAB possessed significantly greater surface roughness according by AFM (Figure 1). Upon visual inspection, the UHMWPE treated with a 2.5el6 dosage were a slightly more rough at the nanoscale compared to the 1.7el6 dosage. Quantitative surface roughness measurements confirmed such qualitative results (Figure 1, with Ra = average surface roughness, Rz = average z height, Rq = mean square surface roughness, and Rpv = average peak to valley surface roughness). Moreover, the geometry of the nanoscale surface features appeared slightly different with the UHMWPE treated at the higher dose, taller and more sharp. Figures 1 A - 1C show AFM Characterization of the Unmodified and ANAB Modified UHMWPE.

Surface Energy ANAB successfully created surface energies closer to that of key endogeneous proteins that reduce wear (lubricin), prevent bacteria from communicating with each other and forming biofilms (mucin), inhibit bacteria colonization (casein) and decrease bacterial adhesion and proliferation (lubricin). In fact, the surface energy of the ANAB modified samples were close to twice that of the control UHMWPE. Both of the ANAB modified samples possessed similar surface energies (Table 1)

Table 1: Surface Energy of the UHMWPE (PE) Samples

Protein Adsorption Results of this study further confirmed that the ANAB treated samples competitively adsorbed more lubricin, mucin, and casein than the unmodified UHMWPE samples (Table 2). Specifically, the ANAB modified surfaces adsorbed up to 8X, 3X, and 2X lubricin, mucin, and casein compared to the control UHMWPE. Both of the ANAB modified surfaces adsorbed similar amounts of proteins.

Table 2: Initial Protein Adsorption (Arbitrary Intensity Values) to the UHMWPE (PE) Samples

Wear Properties

Results of the present study showed that the ANAB treated UHMWPE significantly reduced weight loss compared to the control (Table 3). In fact, no weight loss was determined from the ANAB treated sample presumably due to the aforementioned ability to promote the adsorption of lubricin which improved lubrication due to its optimal surface energy. Table 3: Improved Wear Properties for ANAB Treated UHMWPE (PE)

Bacterial Assays

Results demonstrated significantly less bacteria colonization after 24 hours. Figure 2 shows bacteria colonization on the unmodified and ANAB modified Polyethlyene after 24 hours. 1.7e^ and 2 5e ' ^ refer to the two ANAB doses used. SA = Staph aureus , Pseudomonas = Pseudomonas aeruginosa , and SE = Staph epidermidis. Data = mean +/- SEM; N = 3; all values statistically (p<0.01) different than each other within each bacteria, except for MRSA and E. coli for the two ABAN treated samples. Specifically, over a 2 log reduction in multi-drug resistant E. coli, E. coli, MRSA, and Staph aureus colonization after 24 hours was observed on ANAB modified compared to unmodified UHMWPE.

Discussion

ANAB is a surface modification technique that can create controllable nanoscale features on a versatile array of materials. As has been widely demonstrated, nanoscale surface features can alter material surface energy without changing surface chemistry, important implications for receiving FDA 510(k) clearance. Such changes in surface energy can be easily controlled by the degree and geometry of nanoscale surface features. Importantly, this change in surface energy can increase the selective adsorption of proteins important for mediating cell response, which in turn can reduce infection by limiting bacteria colonization, and promote the adsorption of key endogenous proteins (like lubricin) to reduce wear. The present disclosure demonstrated less bacteria and improved wear for ANAB modified UHMWPE compared to untreated controls. Specifically, ANAB of two different power doses were further used to create different nanoscale surface features and consequent surface energies, as compared to each other and control UHMWPE samples. When comparing the two ANAB modified surfaces, some minor differences were observed but both of the ANAB UHMWPE surfaces improved the adsorption of lubricin to in turn improve wear properties. Further, both ANAB UHMWPE surfaces reduced bacterial colonization. Further studies will have to determine why as differences in surface energy and protein adsorption were minimal or statistically the same between the ANAB modified samples. It is possible that the changes in nanoscale geometry may be the reason (specifically, with the higher ANAB dose presumably providing taller sharper nanoscale features than the lower dose). Differences in nanoscale surface feature geometries have been shown to influence such cell responses in other studies. Nonetheless, it was abundantly clear from the current in vitro study that subtractive ANAB is an easy- to-use, effective, non-coating, non-antibiotic, and non-drug approach to improve UHMWPE properties (such as improved wear resistance and decreased bacteria colonization) for numerous orthopedic applications.

Conclusions The present disclosure demonstrates that UHMWPE can be treated by Accelerated Neutral Atom Beam (ANAB) to generate a surface energy closer to the surface energy of key proteins contained inthe body to improve wear properties (lubricin) and decrease bacteria colonization (mucin, casein, and lubricin). In turn, improved wear properties and inhibited bacteria colonization (including gram positive, gram negative and antibiotic resistant bacteria) after 24 hours was determined for ANAB treated UHMWPE, achieved without resorting to the use of antibiotics. Such results are significant as they were demonstrated for gram positive, gram negative, and multi-drug resistant bacteria. Such results suggest that ANAB modified UHMWPE will be beneficial for a wide range of improved orthopedic applications.

What is claimed is:

Claims

Claims:

1. A method of treating an orthopedic implant, comprising: irradiating a surface of the orthopedic implant with a high energy neutral beam; and controlling the high energy neutral beam to modify nano-scale roughness characteristics of the surface and match the roughness characteristics to a surface energy of a lubricious substance in the implant usage environment.

2. The method of claim 1, wherein the roughness characteristics comprise average surface roughness (Ra), average of height (Rz), mean square surface roughness (Rq) and average peak- to-valley roughness (Rpn).

3. The method of claim 1, wherein the irradiating is performed prior to implantation of the implant in a mammal.

4. The method of claim 1, comprising controlling the high energy neutral beam to establish a surface energy of the surface to match the surface energy of the lubricious substance.

5. The method of claim 1, wherein the irradiating comprises irradiating the entire orthopedic implant.

6. The method of claim 1, wherein the irradiating comprises irradiating a portion of the orthopedic implant.

7. The method of claim 1, wherein the lubricious substance comprises a lubricious protein.

8. The method of claim 1, wherein the lubricious substance comprises an endogeneous inherently present synovial fluid content of a mammalian joint region.

9. The method of claim 1, wherein the lubricious substance comprises an endogeneous synovial fluid introduced into a mammalian joint region.

10. The method of claim 1, wherein the irradiation reduces rubbing of the implant and debris shedding from the implant in a mammalian joint region.

11. The method of claim 1, wherein the implant comprises an ultra-high molecular weight polyethylene (UHMWPE) orthopedic implant device.

12. The method of claim 1 wherein the neutral beam is as accelerated neutral atom beam.

13. The method of claim 12 comprising: forming a gas cluster ion-beam including ionized gas clusters in a reduced pressure chamber containing an ultra-high molecular weight polyethylene (UHMWPE) implant device; accelerating and forming the gas cluster ion-beam along a beam path; at least partially disassociating the gas-cluster ion-beam along the beam path by increasing the range of velocities of ions in the beam; separating the beam leaving essentially only neutral atoms in the beam to irradiate at least a portion of implant surface of the implant with the beam.

14. The method of claim 13 wherein the beam comprises inert gas atoms.

15. The method of claim 14 wherein the inert gas is argon.

16. An orthopedic implant as treated by the method of claim 1.

17. A method of treating an orthopedic implant, comprising: irradiating a surface of the orthopedic implant with a high energy neutral beam; and controlling the high energy neutral beam to establish a surface energy of the surface to match the surface energy of a lubricious substance in the implant usage environment.

18. The method of claim 17, wherein the lubricious substance comprises an endogeneous inherently present synovial fluid content of a mammalian joint region.

19. The method of claim 17, wherein the lubricious substance comprises an endogeneous synovial fluid introduced into a mammalian joint region.

20. The method of claim 17, wherein the irradiating comprises: forming a gas cluster ion-beam including ionized gas clusters in a reduced pressure chamber containing an ultra-high molecular weight polyethylene (UHMWPE) implant device; accelerating and forming the gas cluster ion-beam along a beam path; at least partially disassociating the gas-cluster ion-beam along the beam path by increasing the range of velocities of ions in the beam; separating the beam leaving essentially only neutral atoms in the beam to irradiate at least a portion of implant surface of the implant with the beam.