WO1999052586A1

WO1999052586A1 - Tether anchor

Info

Publication number: WO1999052586A1
Application number: PCT/US1999/008088
Authority: WO
Inventors: David Watson
Original assignee: Cytotherapeutics, Inc.
Priority date: 1998-04-13
Filing date: 1999-04-13
Publication date: 1999-10-21

Abstract

This invention provides novel tether anchors for securing implantable encapsulation and polymer release devices.

Description

TETHER ANCHOR

RELATED APPLICATIONS

This application claims priority under 35 U.S. C. § 119(e) to United States Provisional Application 60/081,617, filed April 13, 1998.

FIELD OF THE INVENTION

The present invention relates to tether anchors for use with encapsulation devices.

BACKGROUND OF THE INVENTION

Implanted encapsulation devices and polymer release devices are being investigated for clinical efficacy in a number of disease indications. These devices often contain an active portion from which the therapeutic is delivered, along with a non-active tether portion, which is used to retrieve the device from the patient. While the tether typically also is used to secure the device in the patient to prevent the device from migrating from its implant location, there is a need for a tether anchor that is small, inexpensive, and that can secure the tether to provide additional protection against undesired device migration from the implant location.

SUMMARY OF THE INVENTION The invention disclosed herein provides a novel tether anchor that can be safely and easily installed and removed, and that can secure the tether and device to prevent undesired device migration from the implant site. The tether anchor has a base and a cap which can be fixedly attached to the base. In one embodiment, the cap is attached to the base by compression fit, although other attachment means, e.g., screw fit, ultrasonic welding, and adhesive means are also contemplated.

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SUBSTΓΠJTE SHEET (RULE 26) BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows one embodiment of the tether anchor. Panel A is a top view showing the tether anchor base (10), and cap (20). Panel B is a side view of the base and cap.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

We initiated efforts to develop a method of securely anchoring the tether of the intrathecally implanted device to prevent undesired device migration in mammalian implants, preferably human patients. The tether anchor described here was designed to be used by physicians who had no experience in securing implantable devices.

Typically, the tether anchor prototypes consist of two pieces, a base and a cap. The device tether is inserted into the base, and the cap is snapped in place to secure the tether within the anchor by compression.

In one embodiment, the tether anchor, designated a Mark 1, consists of two pieces, both made from medical grade acetal resin. The base plate (10) is 0.88 inches long, 0.51 inches wide, and 0.05 inches thick. It has four 0.093 inch diameter suture holes (30) placed one on each corner. A centrally located 0.48 inch diameter collar (40) terminating in a circumferential hook extends upward from the plate 0.14 inches. The collar contains 6 slots (45) which allow the device tether to exit the anchor and facilitate the bending displacement of the hook, thereby allowing a snap fit retention of the anchor top (20). A centrally located 0.055 inch diameter hole (50) in the base allows the tether to pass into the anchor.

The cap of the Mark 1 tether anchor is 0.47 inches in diameter, and 0.153 inches thick. It has a circumferential groove (60) on the side that allows a snap fit retention of the cap onto the base. Installation of the cap on the base captures, by means of compression, the device tether between a series of curved surfaces in order to immobilize the device tether without compromising tether integrity. As noted above, it will be understood that other means of attaching the cap to the base are contemplated, including screw fit, ultrasonic welding, and adhesive means .

It will also be understood that the precise dimensions and configuration of the base and the cap detailed above are representative, and other dimensions and configurations that provide a means for anchoring the tether of an implantable device are within the scope of this invention.

In a second embodiment, the tether anchor, designated the Mark 2, is fabricated from similar biocompatible materials, using similar machining methods, to the Mark 1 prototype. The

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SUBSTΓΓUTE SHEET (RULE 26) base area is similar but the overall height is about 36% less. In addition, the slots in the ring are tapered to provide an additional area for tether retention. It was thought that both of these changes would mimmize the chance of tissue erosion and/or devascularization following suturing of the tether anchor to the lumbodorsal fascia when the device is implanted intrathecally. A secondary lock was also incorporated into the exit slots of the base collar by tapering the width of the slots using dimensions derived from the wedge tether anchor. The dimensions and critical characteristics of these tether anchors are shown in Table 1.

Table 1 : Mark 2 Tether Anchor Dimensions

Prototype

Component Mark l Mark 2B

Base length (in) 0.88 0.88 width (in) 0.51 0.60 thickness (in) 0.05 0.05 central tether hole (in) 0.055 0.055 suture hole diameter (in); 4 each 0.093 0.094

Collar diameter (in) 0.48 0.395 height (in) 0.14 0.065 hook circumferential circumferential slots, 6 straight tapered

Cap diameter (in) 0.47 0.60 thickness (in) 0.153 0.095 groove circumferential circumferential

Assembled anchor height (in) 0.235 0.15

The anchor consists of two pieces, a base and a cap, both made from a polymer (preferably acetal homopolymer or polysulfone, most preferably polysulfone). The base measures 22.4 by 15.2 mm. It has four diameter suture holes, one placed in each corner. A round, centrally- located, ridge with a circumferential hook to mate with the cap contains 6 tapered slots which allow the device tether to exit the anchor. A centrally located 1.4 mm diameter hole in the anchor base allows the tether to pass into the anchor.

The cap for Mark 2 tether anchor has a circumferential groove on the inside that allows a snap fit retention of the cap onto the base. Placing the top on the base captures, by means of compression, the device tether between a series of curved surfaces in order to immobilize the

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SUBSTTTUTE SHEET (RULE 26) device tether without compromising tether integrity. The closing action of the top to the base achieves a secondary compression on the tether by forcing it into the tapered slot. The overall height of the assembled Mark 2 anchor is 4.1mm.

The tether anchors may be conveniently manufactured using Computer Numerical Control equipment. Tether anchor bases and caps are ultrasonically cleaned with 70% isopropanol for 30 minutes, then rinsed with purified water, air dried and packaged for sterilization. The packaged tether pieces are steam sterilized at 121°C for 30 minutes.

In one embodiment, a tether anchor (designated the Mark 2B tether anchor) consists of two pieces which are both made from medical grade acetal resin. The base plate is 0.88 inches long, 0.60 inches wide, and 0.05 inches thick. It has four 0.094 inch diameter suture holes, placed one on each corner. A centrally located 0.395 inch diameter collar, terminating in a circumferential hook, extends 0.065 inches upward from the plate. The collar contains 6 slots which allow the device tether to exit the anchor and facilitate the bending displacement of the hook, thereby allowing a snap fit retention of the anchor cap. In addition, the slots in the ring are tapered to provide an additional area for tether retention. An additional raised ring protrudes upward from the base 0.020 inches and circumscribes the collar at a diameter of 0.545 inches. The design intent of this ring was to reduce the gap between the outer perimeter of the cap and the base and prevent the cap from being cocked to one side during installation. However, testing of the Mark 2B anchors showed that it was possible that the ring could prevent the cap from fully engaging the base. In addition, during implantation surgery in animals, the loose ends of the sutures used to secure the base would sometimes overlie this ring which complicated the engagement of the cap. A centrally located 0.055 inch diameter hole in the base allows the tether to pass into the anchor.

The cap of the Mark 2B tether anchor is 0.60 inches in diameter and 0.095 inches thick. It has a circumferential groove on the bottom side that allows a snap fit retention of the cap onto the base. Installation of the cap on the base captures, by means of compression, the device tether between a series of curved surfaces in order to immobilize the device tether without compromising tether integrity.

In a further embodiment, a tether anchor (designated the Mark 2C tether anchor) is fabricated from identical materials, using similar machining methods, as the Mark 2B prototype. The base area is identical with the exception that the outer circumferential ring has been removed. Removal of the ring did not compromise the snapping of the cap onto the base; rather, the integrity of the closure was enhanced. At the same time, the bottom surface of the base was

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SUBSTΓΓUTE SHEET (RULE 26) increased in thickness by 0.010 inches to improve its rigidity and reduce deflection when the cap is installed. Only dimensional tolerance changes were made to the cap.

The tether anchors described herein may be machined from any suitable biocompatible material, but are preferably machined acetal homopolymer ("AH"), and most preferably fabricated from polysulfone.

In one embodiment, a tether anchor designated model Mark 2C, machined from acetal homopolymer (AH), has been used in a series of more than 70 patients enrolled in clinical trials for an encapsulation device that secretes a cocktail of analgesic factors.

Polysulfone tether anchors (designated herein as Mark 2D) offer an advantage due to the translucence of the material. Investigators can visually verify the correct placement of the anchor while it is being secured to the patient. In one embodiment, the tether anchor is made from polysulfone, which has been used in implantable medical device because of its biologically inert properties and ease of fabrication. Material requirements for medical grade PS (ASTM 702-93) include limits of extractables (21 CFR 177.1655) and documentation of biocompatibility (ICH Guidelines 10993), sterility and lack of pyrogenicity. The polysulfone used in Mark 2D tether anchor meets these requirements.

Polysulfone extruded rods are produced from Udel resin to meet MIL-P-46120 standards for Type 1, Class 2 polysulfone (extrusion, without reinforcement). The physical characteristics of the material are shown in Table 2.

Table 2: Characteristics of Extruded Polysulfone

Characteristic

Chemical 4,4'-isopropyiidone diphenyl and 4,4'- dichlorodiphenyl sulfone

Tensile modulus at break (minimum) 2300 mPa (3.4 x10⁶ psi) Flexural yield strength (minimum) 65 mPa (9500 psi) Percent elongation (minimum) 20 %

Extraction testing of the polysulfone stock shows extractables below the limits set in 21 CRF 177.1655. The results of the tests and limits are show in Table 3. Table 3: Polysulfone Extractables

Compound Limit Result

Dimethyl sulfoxide <55 ppm 18.3 ppm Monochlorobenzene <500 ppm 310 ppm N-methyl-2-pyrrolidone <100 ppm 35.9 ppm

The polysulfone anchor described here, in combination with an encapsulation device, have been evaluated for biocompatability tests in accordance with recommendations of the Tripartite Biocompatibility Guidance for Medical Devices and Biological Evaluation of Medial and Dental Materials and Devices (ISO 10993). The combination of materials has been shown to be non-reactive in in vitro and in vivo testing completed to date.

For purposes of evaluating the tether anchors, we used tethers made from an extruded aliphatic polyurethane, and having an internal diameter of 450 μm and outer diameter of 1150 μm. This material is elastomeric and has a tensile strength of about 5 kg. The tethers had previously been cleaned with isopropyl alcohol and were used without further processing.

To assemble the tether anchors on the tethers, individual tethers are placed within the central hole of the anchor base such that at least 7 cm of the tether remains below the base and about 0.5 cm extends out of the anchor. The upper end of the tether is then placed in a slot in the anchor base, and the cap is securely fitted in place. A 'click' is felt when the cap is placed correctly.

The tensile retention force of the tether anchors are measured using the electromechanical tension-compression material testing system (Instron) at a cross-head speed of 125 mm/min. The upper grip is set about 3 inches above the lower grip at the beginning of the test. The tether anchor is suspended on top of the upper gripper so as not to crush the anchor. The tether is grasped by the lower gripper and the crosshead activated. Since the tether may gradually slip through the anchor, elongation is irrelevant to the performance. Only tensile force is measured.

The extraction force is the peak force observed when the tether is extracted from the anchor. The maximum force is limited by the retention properties of the tether anchor and by the tensile strength of the tether. Therefore, if the tether breaks before the tether is fully extracted from the anchor, the extraction force assigned for that test is indicated as greater than the tensile strength of the tether material. The tether breakage force is recorded.

Tether/anchor assemblies were removed from the incubator and tested within 1 minute using an electro-mechanical tensile-compression material-testing machine (Instron Model 4464).

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SUBSTΓΓUTE SHEET (RULE 26) Briefly, the tether/anchor assembly was nested into the top pneumatic grip using an anchor support. The tether extruding from the central hole of the anchor base was grasped in the lower grip 5 cm from the anchor base. The top grip holding the tether was retracted until the tether pulled out of the anchor. The force required to extract the tether from the anchor is considered the anchor tether retention force.

Data from these studies is shown in Table 4 below. The tether retention capacity of the polysulfone anchor is slightly greater than the acetal homoploymer anchor under all conditions. This may be due to the slight difference in the surface lubricity of the two polymers with the polysulfone less "slippery" than the acetal homoploymer. No change in tether retention force was seen after 4 or 10 weeks in vivo for either version of the anchor.

Table 4: Tether Retention Force for PS and AH Tethers Anchors

Condition Time Polysulfone Anchor Acetal homopolymer Anchor (Mark 2D) (Mark 2C)

In vitro 1 day 2.22 ± 0.08 kg 1.73 ± 0.05 kg

In vitro 30 days 2.22 ± 0.10 kg 1.67 ± 0.06

In vivo 4 weeks 2.25 ± 0.10 kg (sheep) 1.66 ± 0.05 (sheep)

In vivo 10 weeks 2.22 ± 0.22 kg (sheep) 1.53 ± 0.15 kg (humans)

The polysulfone anchors easily permitted verification of the anchor base over the tether insertion site. In addition, the translucence of the anchor base facilitated location of the anchor base holes with the suture needle during fixation.

Polysulfone tether anchor performance is equal to or better than the acetal homopolymer anchor in vitro and in vivo. The polysulfone anchor has an advantage in clinical applications in that the translucence of the material permits the implanting physician an opportunity to verify that the anchor is properly positioned over an intrathecal tether insertion site (in this case in the lumbodoral fascia).

Tethered implantable devices that may be secured upon implantation are well known in the art, and are described, e.g., in United States patent Nos. 5,800,828; 5,283,187; 5,656,372; 5,773,286; 5,653,975; 5,795,790, each fully incorporated herein by reference.

The tether anchors of this invention may be affixed to the mammalian host (preferably human patient) using a variety of affixation means. In a preferred embodiment, the tether anchor has one or more suture holes in the base or cap, preferably the base to permit suturing to the host. Other affixation means, such as adhesive tape, stapling means, are also contemplated for use with the tether anchors of this invention.

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SUBSTΠTJTE SHEET (RULE 26) Implantable devices are contemplated for a variety of implant locations, including subcutaneous, intravenous, intramuscular and intrathecal locations. Accordingly, the tether anchors described here are adapted for affixation to the appropriate implant in the host.

EXAMPLE 1 - Testing the Tether Anchors In Vitro

Mark 1 and Mark 2B anchors were tested for extraction force after 1 day of incubation in culture medium (HBSS) in vitro. The tether extraction force for the Mark 2B anchor was significantly more that for the Mark 1 anchor, 1.87 ± 0.11 kg versus 0.96 ± 0.12 kg respectively (pθ.0001, Student's t-test). The tensile retention force of the tether anchors was measured using the electromechanical tension-compression material testing system (Instron) at a crosshead speed of 125 rnm/min. The upper grip was set approximately 1 inch above the lower grip at the beginning of the test. The tether anchor was suspended on top of the upper gripper to prevent crushing the anchor. The tether was grasped by the lower gripper and the crosshead activated. Since the tether may gradually slip through the anchor, elongation was irrelevant to performance. Only tensile force was recorded.

The extraction force was the peak force observed when the tether was extracted from the anchor. The maximum force was limited by the retention properties of the tether anchor and by the tensile strength of the tether. The Mark 1 and Mark 2B anchors were also tested for extraction force after a minimum of 14 days of incubation in culture medium in vitro. The tether extraction force for the Mark 2B anchor was significantly more that for the Mark 1 anchor, 1.77 ± 0.05 kg versus 1.02 ± 0.07 kg respectively (pO.OOOl, Student's t-test).

There was no statistical difference between the extraction force of anchors Mark 1 tested at 1 day and those tested at 14 days (p = 0.1798). The extraction force for the Mark 2B tether anchors with day 1 of incubation was statistically different that that observed after 30 days of incubation (1.87 ± 0.11 vs 1.77 ± 0.05,/?=0.0336). Although statistically significant, this difference (approximately 5% difference in the means) is not believed to be clinically significant and the statistical significance of the difference is attributed to the very narrow relative standard deviation for the data (< 6% rsd at lday and < 3% rsd at 30 days) obtained for the Mark 2B anchors.

Tether-anchor assemblies for a Mark 2B and 2C were also compared by incubation for 30 days at 37°C in HBSS. Each anchor was removed from the incubator and tested within 5 minutes

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SUBSTΓΓUTE SHEET (RULE 26) for tether extraction force. The average tether extraction force for the Mark 2B anchor was significantly more that for the Mark 2C anchor, 1.77 ± 0.05 kg versus 1.66 ± 0.05 kg, respectively (p<0.00\, Student t-test).Individual tether segments were placed within the central holes of the Mark 2C anchor bases with at least 7 cm of the tether remaining below the base and about 0.5 cm extending upwards. The upper end of the tether was then placed in a slot in the anchor base, and the cap was securely fitted in place. A 'click' was felt when the cap was placed correctly in the bases. The tether-anchor units in each group were then placed in a petri dish containing HBSS and labeled. The labeled dishes were placed in a incubator maintained at 37°C. The mechanical properties of the Mark 2C tether anchor have been evaluated by measuring the force required to extract the tether from the assembled anchor and compared to previously tested Mark 2B tether anchor. The tests were performed after incubation of the tether- anchor units in buffer at 37°C 30 days and after 14 days in vivo with an additional 14 days incubation.

When the extracting forces of Mark 2C tether anchor were compared to those of the Mark 2B anchor after 30 days in vitro incubation, the Mark 2C tether-anchor assembly was slightly lower (0.11 kg). Although statistically significant, this difference (approximately 6% difference in the means) is not clinically significant. The statistical significance of the difference is attributed to the small standard deviations for the data (coefficient of variation < 3%) obtained for both the Mark 2B and Mark 2C anchors. When the extraction forces of Mark 2C tether anchor were compared to those of the Mark

2B anchor after 14 days in vivo and an additional 14 days incubation, the Mark 2C tether-anchor assembly was slightly lower (0.387 kg). However, this difference was not significant.

The extraction force for the polysulfone Mark 2D and acetal homopolymer Mark 2C tether anchors was compared by a Student's t-test for each of the two incubation periods. In addition, the extraction force for each prototype was compared for 1 and 30 days incubation at 37°C. The tether retention characteristics of two versions of the Mark 2 tether anchor were determined and compared. Prototype Mark 2D anchors (made from polysulfone) were compared to the current Mark 2C anchors (made from acetal homopolymer). The manufacturing process and dimensional characteristics were otherwise identical. The polysulfone anchors had a statistically higher tether retention force than the acetal anchors at 1 and 30 days. Additionally, both anchor types had statistically equivalent retention forces and 1 and 30 days.

- 9 - SUBSTΠTJTE SHEET (RULE 26) EXAMPLE 2: Testing In Vivo

Encapulation devices with a polymer tether are surgically implanted, under local anesthesia, into the subarachnoid space of the spinal cord at the L3-L4, L4-L5, or L5-S1 level. A sterile surgical insertion kit consisting of a 19-gauge Tuohy needle, dilators, cannula, stainless steel pusher, spatula and guidewire is provided with the device. A sterile polymer tether anchor is provided for each implantation.

The Tuohy needle is inserted at an appropriate angle to pass between the vertebrae at the L3-L4 or more caudal level, through the ligamentum flavum and into the subarachnoid space. The guidewire is then inserted through the lumen of the needle. The needle is retracted and an over-dilator is placed over the guidewire. This dilator is removed and a dilator-cannula assembly is introduced over the guidewire. The guidewire and dilator are removed, leaving the cannula in place. The device is inserted through the cannula into position in the subarachnoid space.

The tether is initially secured and the tether track closed using a nonabsorable pursestring suture of 0 Mersilene material. The base of a two-part sterile tether anchor is removed from the packaging and introduced into the surgical field. The free end of the tether is then placed through the central hole in the tether anchor base plate and the base plate is passed down the tether until the smooth surface is applied against the lumbodorsal fascia with the central hole directly overlying the site where the tether emerges from the fascia. The anchor base plate should then be sutured securely to the lumbodorsal fascia using 0 Mersilene sutures placed at the 4 suturing holes. After the base plate is properly secured, the free portion of the tether is placed into one of the radial slots in the plate and the cap is fitted with its smooth, rounded surface facing the operator. The tether is then trimmed approximately 1 cm from the margin of the anchor cap and the short section of the free tether is anchored with Mersilene suture to one of the suture holes in the base plate. The device and anchor are then completely covered with a two- layer closure of the subcutaneous tissue and skin. Additional details regarding the implantation procedure are included in the study protocol. Inadequate suturing of the anchor may result in device migration and potential breakage.

Explanation is performed under local anesthesia in sterile conditions in a controlled environment. The implantation incision is opened sharply down through the dermis. Sharp dissection is used to fully expose the tether material down to the level of the lumbodorsal fascia. A 5 mm opening in the lumbodorsal fascia is made at the tether, enlarging the tether track through the fascia. The sutures securing the anchor base are cut and the tether and anchor are then withdrawn from the subarachnoid space using minimal traction on the tether. The opening

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SUBSTTΠJTE SHEET (RULE 26) of the track from which the device emerged is securely closed with suture.

Typically, in the testing of these tether anchors, the experimental design called for the use of female or castrated male Ovis ares (domestic sheep) who were less than five years old and weighed at least 50 kg. Nineteen females (Phases 1, 2, and 4) and six castrated males (Phase 3) were used in this study.

Animals were to be held in quarantine for approximately seven days prior to the implantation procedure. The animals were actually held seven to ten days. During this time, a physical examination was performed on each animal to assess general body condition. Each animal was identified by a unique number which was noted on the animal's ear tag and on the cage in which the animal was housed.

Animals were housed indoors with a dark/light cycle consistent with Eastern Standard Time. Room temperature was maintained at 64-78°F; humidity range was maintained at 30- 70%. The room was ventilated with 10-15 changes/hr. Sheep were fed hay twice daily and Rumilab Chow® once daily. Fresh tap water was available ad libitum. Animals were fasted the evening prior to any surgical procedure.

Rectal body temperature and body weight measurements were determined for each animal prior to implantation. The rectal temperature of one animal (#357, Phase 3) was determined but not recorded at the time of implantation.

Each animal was sedated (10 mg acepromazine with 2.16 mg atropine IM) and anesthetized (sodium pentothal induction, with inhaled halothane or isoflurane anesthesia). After sedation, a prophylactic antibiotic (1 g cefotaxime) was administered intravenously. Intrathecal Implantation The skin of each sheep was incised to the lumbodorsal fascia. A Tuohy needle was then introduced into the subarachnoid space at a lumbar level and directed at a 30-35 angle with respect to the spinal cord. The guidewire was then passed down the lumen of the needle and advanced 4-5 cm into the subarachnoid space. Upon proper placement of the guidewire, the

Tuohy needle was withdrawn. An overdilator was placed over the guidewire and directed through the fascia, paraspinous muscle, and ligamentum flavum into the subarachnoid space.

After passing the ligamentum flavum, the dilator was removed. A dilator and cannula sheath was assembled, placed over the guidewire, and advanced into the subarachnoid space until the cannula tip was lying 9-11 cm within the space. After appropriate positioning of the cannula, the guidewire and dilator were removed.

If there was no spontaneous flow of CSF from the cannula, or if the flow was excessively

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SUBSTΠTJTE SHEET (RULE 26) bloody or slow, the implantation procedure was not performed at that site. For this reason, one animal (W530, Phase 2.A) received only one intrathecal device. After correct placement of the cannula, the 7.0 device was removed from its packaging, transferred to the Lumbar Surgical Implantation Kit tray and maintained in fresh Hank's Buffered Salt Solution (HBSS). The device was carefully introduced into the cannula and advanced until the tip of the membrane reached a point that was 2 mm within the cranial tip of the cannula in the subarachnoid space. The entire tether and membrane portion of the device were held stationary while the cannula was withdrawn. The device and about 2 cm of the tether remained positioned within the subarachnoid space, while the remainder of the tether extended externally through the ligamentum flavum, the paraspinous musculature, and the lumbodorsal fascia.

To anchor devices, the external end of the tether was inserted into the tether anchor at the 15 cm positioning mark and the anchor was sutured to the fascia. The skin was then closed, leaving no transcutaneous components. Implantation of Intramuscular Devices

An incision was made, cranial to the site of implantation of the intrathecal devices, incising the skin and subcutaneous tissues down to the lumbodorsal fascia. The tether-only devices were implanted intramuscularly 5 cm into the paravertebral muscle cranial to the intrathecally implanted devices. The external free portion of each intramuscular tether was attached to one of the four titanium tether anchor prototypes at the level of the fascia. The anchors were secured to the fascia at each suture point. The ends of the tethers were also sutured to the fascia. The skin was then closed, leaving no transcutaneous components. Monitoring and Explantation Each animal in this study was monitored on a routine basis for possible injury, illness or postoperative complications. The animals were monitored at the following time points: preimplantation, day 1 postoperatively, and weekly until the animals were explanted.

Animal behavior was documented, noting any of the following: agitation, arching/rigid neck, weak/unstable hind limbs, weak unstable forelimbs, failure/reluctance to weight-bear normally (noting the affected limb), or changes in appetite or stool/urine production. In addition, the condition of the surgical wound(s) was examined and noted. All other clinically apparent abnormalities were noted as well. If no abnormalities were noted, this was also recorded. Intrathecal and intramuscular devices were generally explanted at either two or four

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SUBSTΠTJTE SHEET (RULE 26) weeks (± 4 days) postimplantation (n=29). Implant and explant procedures were performed on the same day in one animal (0952, Phase l.B).

Rectal body temperature and body weight measurements were determined on each animal prior to explanation. The sheep were anesthetized and positioned on the operating table as for the implantation procedure. Explanation surgery was performed under sterile conditions. The skin was incised and the tethers of the devices were exposed down to the lumbodorsal fascia. An approximate 5 mm opening was made in the lumbodorsal fascia next to each tether. The tissue at the implant site(s) was visually inspected for signs of toxicological effects. In addition, the condition of the external and internal surgical wound(s) (including evidence of drainage, infection, or hematoma), anchors (including position of anchor, evidence of buckling or adherent tissue), and sutures (whether or not anchor sutures were still intact) were evaluated. Samples of the tissue surrounding both anchors were taken from sheep 31 (Phase 3), but were not analyzed as no clinically signficant findings were noted at the time of explanation. Prior to retrieval of the devices, the tethers, with or without attached anchors, were visually inspected for position. The degree of tether migration was determined for all devices. The sutures used to secure the anchors to either the fat or the fascia were cut with an electrocautery instrument prior to removal of the devices. Each device was then withdrawn by simple traction on the tether. Upon retrieval, the devices and the tether anchors were visually inspected for integrity and then immediately placed in transport media (CHO-S-SFM with penicillin/streptomycin) for analysis.

Healthy sheep that showed no evidence of clinically sigmficant abnormalities were allowed to recover and were either used in another reimplantation study (as in Phase 1.A animals) or were donated to a local farm. Sheep with clinically significant findings were euthamzed. None of the 12 intrathecally implanted devices that had been secured with either a Mark

2B or a Mark 2C prototype migrated after two weeks in vivo. It is possible that the use of a purse-string suture around the tether to reduce the likelihood of leakage of CSF may also have prevented device migration. The ease of installation of the Mark 2C acetal resin tether anchor was assessed descriptively. In all the ammals, the caps snapped to the bases with ease and produced an audible "snap".

Six tethers removed from Mark 2C acetal resin anchors were explanted after 2 weeks implantation in sheep and used for microscopic studies. Devices had been secured with a purse- string suture and tether anchor. The anchor caps were removed and the tethers were visually

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SUBSTΓΓUTE SHEET (RULE 26) examined for gross defects after removal from the anchor base.

Samples were examined and representative SEM's were taken at three segments of each tether. The "A" region was defined as the point where the tether entered the bottom side of the anchor base, the "B" region was defined as the area within the anchor where the tether was constrained by compression and the "C" region was where the tether exited the perimeter of the anchor. All tethers were free of any visible defects at the entrance site to the base and within the compressed region B. Pronounced compression sets were noted on all samples at the exit site C at the perimeter of the anchor. After removal from their anchor, all tether samples maintained a distorted shape as a result of the bending and compression within the anchor similar to what was seen with the Mark 2B anchors. The compression set noted at the exit site C was more defined than the set noted within region B. The location of the tether length mark in relation to the anchor varied slightly within the samples (approximately 3 mm to 6 mm external to region A), but was deliberately maintained outside the anchor at time of implant.

All six samples were shown by SEM to be free of untoward damage caused by the anchor. SEM analysis of region A revealed no signs of tether damage due to the entrance site of the anchor. Similar to what was seen with the Mark 2B in Region B, under high magnification (50x and greater), the impression of the fine machine surface finish of the acetal anchor can be detected in the surface of the polyurethane tether. In 2 of 6 samples, an additional surface crease was noted at the transition point from region A to region B. This surface crease corresponds in location to the point on the anchor of the smallest radius and has the appearance of the natural "wrinkle" found on the inner surface of the finger at the knuckle. Since the polyurethane material is under axial compression at this point, it is believed that this mark is a result of compression over time. None of the creases have propagated into the material or beyond this location. This characteristic crease was also noted in all 6 of 6 samples in the Mark 2B anchor study. The reduction in incidence may be a result of the slightly thicker base of the Mark 2C anchor as compared to the Mark 2B anchor and therefore, slightly less acute bend of the tether. SEM analysis of the exit site (region C) revealed the presence of localized surface creases in all tethers. These creases appeared to be caused by compression of the polyurethane against the exit slot in the anchor base. These creases are identical in appearance to those seen on the Mark 2B anchors and are a result of the narrow exit slot in the base which was a deliberate design feature of the Mark 2B and 2C tether anchors. The Mark 1 anchor slots were slightly wider than the tether and installation of the cap was problematic since the tether would naturally slide out of the

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SUBSTTTUTE SHEET (RULE 26) slot while installing the cap. Narrowing the slot provided both a temporary restraining means for holding the tether during installation of the cap and a permanent secondary anchoring means for the tether. There was no evidence of propagation of any of the creases beyond the area of direct contact. The average tether extraction force for the Mark 2B anchor was slightly greater than that for the Mark 2C anchor, 1.455 kg versus 1.068 kg, respectively. However, this difference is not statistically significant (p<0.0667, Student t-test).

There was no incidence of device migration in vivo for any of the Mark 2C or Mark 2B anchors. The average tether retention strength of the Mark 2C anchor was found to be slightly lower than the Mark 2B version in both the 30 day in vitro and 14 day in vivo evaluations. However, this difference is not thought to be clmically significant.

All tether samples recovered from Mark 2B or 2C tether anchors were shown to be free of untoward damage caused by the anchor. SEM analysis of the anchor inlet region revealed no signs of tether damage due to the entrance site of the anchor. Similar to the Mark 2B, under high magnification (50x and over), the impression of the fine machine surface finish of the Mark 2C acetal anchor can be detected in the surface of the polyurethane tether. The incidence of surface creases formed at the compression point in the Mark 2C tethers was reduced as compared to the Mark 2B anchors (2/6 for the Mark 2C and 6/6 for the Mark 2B).

The Mark 2C anchors were superior to the Mark 2B anchors with regard to ease of use and reliability. In another study, 6 sheep were implanted bilaterally with the Mark 2B anchor. The observations at the time of implant of these anchors, revealed an occasional problem fitting the caps on the anchor bases after the tethers had been inserted. Additionally, four Mark 2B anchor assemblies dissociated during in vitro and ex vivo testing. Based on these findings, slight changes in the design of the Mark 2B were made resulting in the Mark 2C. It was determined by a mathematical tolerance study (and confirmed by measurement of the samples) that an interference between an annular feature on the Mark 2B base and the bottom surface of the cap prevented the complete engagement of the retaining hooks that lock the cap to the base. This feature was eliminated from the design of the Mark 2C. No instances of difficulty in assembly, or anchor cap dissociation were noted during testing of the Mark 2C anchors. Polysulfone anchors used to retain implanted CT devices were removed after 4 or 10 weeks in vivo. The explanted tether/anchor assemblies were reincubated at 37°C in Hanks buffer (HBSS) for at least 12 hours before testing (Protocol 650-98).

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SUBSTΓΓUTE SHEET (RULE 26) The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description an accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

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SUBSTΓΓUTE SHEET (RULE 26)

Claims

WE CLAIM:

1. A tether anchor formed from a biocompatible material comprising: a base plate comprising a tether attachment means for attaching a tether of an implantable device within the tether anchor, a cap-engaging means to attach a cap to the base plate, an affixation means for affixing the tether anchor to a host upon implantation in the host, and a cap, the cap comprising base-engaging means that permits mating of the cap to the base, wherein the tether is fixedly secured within the tether anchor when the base and cap are mated.

2. The tether anchor of claim 1, wherein the biocompatible material is acetal homopolymer or polysulfone.

3. The tether anchor of claim 1, wherein the cap-engaging means comprises a circular collar terminating in a circumferential hook and the base-engaging means comprises a circumferential groove.

4. The tether anchor of claim 1 wherein the affixation means comprises suture holes.

5. A method for securing an implantable device to a host in which the device is implanted, comprising attaching to the device a tether anchor according to claim 1, and affixing the tether anchor to the host.

6. The method of claim 5, wherein the tether anchor is affixed using suture means.

7. The method of claim 5, wherein the tether anchor is affixed to the fascia of the host.

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SUBST╬ô╬áJTE SHEET (RULE 26)