Methods for vascular restoration therapy

Abstract

A medical device includes a polymer scaffold crimped to a catheter having an expansion balloon. The scaffold has a structure that produces a low late lumen loss when implanted within a peripheral vessel and also exhibits a high axial fatigue life. In a preferred embodiment the scaffold forms ring structures interconnected by links, where a ring has 12 crowns and at most two links connecting adjacent rings.

Claims

1. A method for making a scaffold for vascular restorative therapy of a peripheral vessel, comprising: making the scaffold comprising forming a polymer tube and forming the scaffold from the polymer tube, wherein the scaffold comprises a pair of rings adjoined by link struts that extend parallel to a longitudinal axis of the scaffold; and crimping the scaffold to a balloon; whereupon implantation of the scaffold in the peripheral vessel by inflation of the balloon the scaffold is plastically deformed to have an expanded diameter, whereupon the scaffold has the following characteristics: between about 8-15% fractured struts after 28 days; K-norm is between about 7 and 15; the expanded diameter is greater than 5 mm; the scaffold has a ratio of the expanded diameter to a wall thickness of about 25:1 to 30:1; and the scaffold has a length greater than 40 mm.

2. The method of claim 1, wherein the polymer tube is a biaxially expanded polymer tube.

3. A method for making a vascular restorative (VR) scaffold for a peripheral vessel of a body, comprising: using a plurality of prior scaffolds, each having a plurality of first rings adjoined by first links, wherein there are a different number of crowns and/or a different number of the first links connecting first rings between at least a first and second of the plurality of the prior scaffolds; measuring a time-varying mechanical property for at least one of the prior scaffolds when the prior scaffold is subjected to at least a periodic axial loading; and using the measured time-varying mechanical property, making the VR scaffold comprising making second rings and second links adjoining the second rings, wherein the second links extend parallel to a longitudinal axis of the VR scaffold, and selecting a strength, stiffness and toughness for the VR scaffold such that the VR scaffold is capable of providing a scaffolding for the peripheral vessel for up to about 3-4 months after the VR scaffold is implanted in the peripheral vessel; wherein the prior scaffold and the VR scaffold are made from the same polymer material.

4. The method of claim 3, wherein the measured time-varying mechanical property is one or more of a number of fractured struts, toughness, radial strength/stiffness or pinching stiffness.

5. The method of claim 3, wherein the made VR scaffold provides a time rate of change in the mechanical property, over the interval of between 28 and 60 days from implantation in the peripheral vessel, of between about 0.0055 to 0.0035.

6. The method of claim 3, wherein the prior scaffolds and the VR scaffold are configured for being crimped to a balloon then plastically deformed to an expanded diameter when the balloon is inflated, and wherein a ratio of the expanded diameter to a wall thickness for the VR scaffold is 25:1 to 30:1.

7. The method of claim 3, wherein the measured time-varying mechanical property is obtained either in-vivo or in-vitro.

8. The method of claim 3, wherein the VR scaffold is made from a biaxially expanded tube the tube is made from a polymer material comprising poly (L-lactide).

9. A method for making a vascular restorative (VR) scaffold for a peripheral vessel of a body, comprising: using a plurality of prior scaffolds, each having a plurality of first rings adjoined by first links, wherein there are a different number of crowns and/or a different number of first links connecting first rings between at least a first and second of the plurality of the prior scaffolds; measuring a time-varying mechanical property for at least one of the prior scaffolds when the prior scaffolds are subjected to at least a periodic axial loading; and using the measured time-varying mechanical property, making the VR scaffold comprising making second rings and second links adjoining second rings, and selecting a strength, stiffness and toughness for the VR scaffold such that the VR scaffold is capable of providing a scaffolding for the peripheral vessel for up to about 3-4 months after the VR scaffold is implanted in the peripheral vessel; wherein the prior scaffolds and the VR scaffold are configured for being crimped to a balloon then plastically deformed to an expanded diameter when the balloon is inflated, and wherein a ratio of the expanded diameter to a wall thickness for the VR scaffold is 25:1 to 30:1; and wherein each of the first rings of the prior scaffolds have between 8 and 12 crowns and no more than 2-3 links, and the second rings of the VR scaffold each have between 8 and 12 crowns and there are no more than 2-3 second links between second rings.

10. The method of claim 9, wherein the measured time-varying mechanical property is one or more of a number of fractured struts, toughness, radial strength/stiffness or pinching stiffness.

11. The method of claim 9, wherein the VR scaffold provides a time rate of change in the mechanical property, over the interval of between 28 and 60 days from implantation, of between about 0.0055 to 0.0035.

12. The method of claim 9, wherein the measured time-varying mechanical property is obtained either in-vivo or in-vitro.

13. The method of claim 9, wherein the second links extend parallel to a longitudinal axis of the VR scaffold.

14. The method of claim 9, wherein the VR scaffold is made from a polymer composition comprising poly (L-lactide).

15. The method of claim 14, wherein the VR scaffold is made from a biaxially expanded tube and the tube is made from the polymer composition comprising poly (L-lactide).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a perspective view of a deformed polymer tube. The tube is formed into a scaffold.

(2) FIG. 2 is a partial planar view of a scaffold pattern according to a first embodiment of a scaffold.

(3) FIG. 3 is a partial perspective view of a scaffold structure.

(4) FIG. 4 is a partial planar view of a scaffold pattern according to a second embodiment of a scaffold.

(5) FIG. 5A is a planar view of a portion of the scaffold pattern of FIG. 4 taken at section VA-VA.

(6) FIG. 5B is a planar view of a portion of the scaffold pattern of FIG. 2 taken at section VB-VB.

(7) FIGS. 6A and 6B are tables showing examples of scaffold features in accordance with aspects of the disclosure.

(8) FIG. 7 compares results from a three-point bending test of a V76 scaffold design to a V62 scaffold and the V59 scaffold described in WO2011094621.

(9) FIG. 8 compares results from a bending fatigue test among the V76, V62 and V59 scaffolds.

(10) FIG. 9 compares the axial force among the V76, V62 and V59 scaffolds for a 10% static compression and extension.

(11) FIG. 10 shows a mean and standard deviation fractures at crowns and links for the V76 scaffold for one month and six month simulated walking tests of the V76.

(12) FIG. 11 compares the radial strength among the V76, V62 and V59 scaffolds.

(13) FIG. 12 compares the radial stiffness among the V76, V62 and V59 scaffolds.

(14) FIG. 13 compares the acute recoil of the V76 scaffold to the V59 and V62 scaffold, and the V2 scaffold described in WO2011094621.

(15) FIG. 14 compares the crush-recovery among the V76, V62 and V59 scaffolds.

(16) FIG. 15 compares the deploy-to-fracture among the V76, V62 and V59 scaffolds. This plot shows that the V76 begins to develop critical fractures at a higher diameter than the V59.

(17) FIG. 16 compares the pinching stiffness among the V76, V62 and V59 scaffolds.

(18) FIG. 17 compares the percentage of discontinuities, fractures or failures of struts and links among several scaffold designs having different numbers of crowns and/or links connecting ring structures. The discontinuities are counted following a six-month simulated walking test.

(19) FIG. 18 counts the total number of discontinuities, fractures or failures of struts and links among the several scaffold designs from FIG. 17, 28 days after being implanted in the animal model.

(20) FIG. 19 compares the in-vivo late lumen loss among several scaffold designs after 28 days implantation.

(21) FIG. 20 provides statistical significance values (t-test) for the late lumen loss in FIG. 19.

(22) FIG. 21 compares the percentage diameter stenosis 28 days following implantation for different scaffolds.

(23) FIG. 22 compares the acute recoil percentage for several different scaffolds.

(24) FIG. 23 shows the radial strength (N/mm) and radial stiffness (N/mm per mm) for the V59, V62, V76, V78, V79 and V80 scaffolds.

(25) FIG. 24 is a flow diagram summarizing a process of Vascular Restoration Therapy (VRT).

(26) FIG. 25A and FIG. 25B show a comparison between the time-varying mechanical properties of a coronary scaffold and peripheral scaffold.

(27) FIG. 26A is a plot showing a change in scaffold crush and recovery for a peripherally implanted V79 and V80 scaffold, as compared to a V59 scaffold.

(28) FIG. 26B is a plot showing a change in scaffold stiffness at 13% crush for a peripherally implanted V79 and V80 scaffold, as compared to a V59 scaffold.

(29) FIGS. 27A and 27B illustrate the dynamics of the femoral artery during normal use of the leg.

DETAILED DESCRIPTION OF EMBODIMENTS

(30) The disclosure provides examples of parameters and characteristics of scaffolds useful as design criterion for promoting favorable vascular restorative therapy (VRT). According to the disclosure there are examples applied specifically to a peripherally-implanted, bioresorbable scaffold. The concepts disclosed, however, are useful for a wider variety of luminal indication such as coronary, intracranial vessels, carotid vessels, venous location such as AV fistula, IVC, airway obstruction, tracheal implant, biliary implant etc.

(31) For purposes of this disclosure, the following terms and definitions apply:

(32) The term about means 10%, 5%, or 2% less or more than a stated value, a range or each endpoint of a stated range, or a one-sigma variation from a stated mean value.

(33) Reference vessel diameter (RVD) is the diameter of a vessel in areas adjacent to a diseased section of a vessel that appear either normal or only minimally diseased.

(34) Minimal lumen diameter (MLD) is the diameter of a diseased section of a vessel at the site of maximal reduction in the diameter.

(35) % Diameter restenosis (% DS) is the percent difference between the reference vessel diameter and the minimal lumen diameter: (RVDMLD)/RVD

(36) Acute gain is defined as the difference between pre- and post-procedural minimal lumen diameter.

(37) Late loss is defined as the difference between minimal luminal diameter after the procedure or post-percutaneous coronary intervention (PCI) and minimal luminal diameter at follow-up.

(38) Inflated diameter or expanded diameter refers to the diameter the scaffold attains when its supporting balloon is inflated to expand the scaffold from its crimped configuration to implant the scaffold within a vessel. The inflated diameter may refer to a post-dilation balloon diameter which is beyond the nominal balloon diameter, e.g., a 6.5 mm balloon has about a 7.4 mm post-dilation diameter, or a 6.0 mm balloon has about a 6.5 mm post-dilation diameter. The nominal to post dilation ratios for a balloon may range from 1.05 to 1.15 (i.e., a post-dilation diameter may be 5% to 15% greater than a nominal inflated balloon diameter). The scaffold diameter, after attaining an inflated diameter by balloon pressure, will to some degree decrease in diameter due to recoil effects related primarily to, any or all of, the manner in which the scaffold was fabricated and processed, the scaffold material and the scaffold design.

(39) Post-dilation diameter (PDD) of a scaffold refers to the diameter of the scaffold after being increased to its expanded diameter and the balloon removed from the patient's vasculature. The PDD accounts for the effects of recoil. For example, an acute PDD refers to the scaffold diameter that accounts for an acute recoil in the scaffold.

(40) A pre-crimp diameter means an OD of a tube, or the scaffold before it is crimped to a balloon. Similarly, a crimped diameter means the OD of the scaffold when crimped to a balloon. The pre-crimp diameter can be 2, 2.5, 3.0 times greater than the crimped diameter and about 0.9, 1.0, 1.1, 1.3 and about 1-1.5 times higher than an expanded diameter or post-dilation diameter.

(41) Recoil means the response of a material following the plastic/inelastic deformation of the material. When the scaffold is radially deformed well beyond its elastic range and the external pressure (e.g., a balloon pressure on the luminal surface) is removed the scaffold diameter will tend to revert back to its earlier state before the external pressure was applied. Thus, when a scaffold is radially expanded by applied balloon pressure and the balloon removed, the scaffold will tend to return towards the smaller diameter it had, i.e., crimped diameter, before balloon pressure was applied. A scaffold that has recoil of 10% within hour following implantation and an expanded diameter of 6 mm has an acute post-dilation diameter of 5.4 mm. The recoil effect for balloon-expanded scaffolds can occur over a long period of time. Post-implant inspection of scaffolds shows that recoil can increase over a period of about one week following implantation. Unless stated otherwise, when reference is made to recoil it is meant to mean recoil along a radial direction (as opposed to axial or along longitudinal direction) of the scaffold.

(42) Acute Recoil is defined as the percentage decrease in scaffold diameter within the first about hour following implantation within a vessel.

(43) The glass transition temperature (referred to herein as Tg) is the temperature at which the amorphous domains of a polymer change from a brittle vitreous state to a solid deformable or ductile state at atmospheric pressure. In other words, Tg corresponds to the temperature where the onset of segmental motion in the chains of the polymer occurs. Tg of a given polymer can be dependent on the heating rate and can be influenced by the thermal history of the polymer. Furthermore, the chemical structure of the polymer heavily influences the glass transition by affecting mobility of polymer chains. A lower end of Tg is Tg-LOW, a midpoint is Tg-MID and upper end is Tg-HIGH.

(44) Stress refers to force per unit area, as in the force acting through a small area within a plane within a subject material. Stress can be divided into components, normal and parallel to the plane, called normal stress and shear stress, respectively. Tensile stress, for example, is a normal component of stress that leads to expansion (increase in length) of the subject material. In addition, compressive stress is a normal component of stress resulting in compaction (decrease in length) of the subject material.

(45) Strain refers to the amount of expansion or compression that occurs in a material at a given stress or load. Strain may be expressed as a fraction or percentage of the original length, i.e., the change in length divided by the original length. Strain, therefore, is positive for expansion and negative for compression.

(46) Modulus may be defined as the ratio of a component of stress or force per unit area applied to a material divided by the strain along an axis of applied force that result from the applied force. For example, a material has both a tensile and a compressive modulus.

(47) Toughness, or fracture toughness is the amount of energy absorbed prior to fracture, or equivalently, the amount of work required to fracture a material. One measure of toughness is the area under a stress-strain curve from zero strain to the strain at fracture. The stress is proportional to the tensile force on the material and the strain is proportional to its length. The area under the curve then is proportional to the integral of the force over the distance the polymer stretches before breaking. This integral is the work (energy) required to break the sample. The toughness is a measure of the energy a sample can absorb before it breaks. There is a difference between toughness and strength. A material that is strong, but not tough is said to be brittle. Brittle materials are strong, but cannot deform very much before breaking.

(48) As used herein, the terms axial and longitudinal are used interchangeably and refer to a direction, orientation, or line that is parallel or substantially parallel to the central axis of a stent or the central axis of a tubular construct. The term circumferential refers to the direction along a circumference of the stent or tubular construct. The term radial refers to a direction, orientation, or line that is perpendicular or substantially perpendicular to the central axis of the stent or the central axis of a tubular construct and is sometimes used to describe a circumferential property, i.e radial strength.

(49) The term crush recovery is used to describe how the scaffold recovers from a pinch or crush load, while the term crush resistance is used to describe the force required to cause a permanent deformation of a scaffold. A scaffold or stent that does not possess good crush recovery does not substantially return to its original diameter following removal of a crushing force. As noted earlier, a scaffold or stent having a desired radial force can have an unacceptable crush recovery. And a scaffold or stent having a desired crush recovery can have an unacceptable radial force. Crush recovery and crush resistance aspects of scaffolds are described in greater detail in US20110190871.

(50) The term crush recovery energy given in units of N*mm refers to the energy or work required to produce the stated amount of crush (as a percentage of the diameter of the scaffold, e.g., 10% crush means the scaffold diameter or height is reduced to 90% of its pre-crush height).

(51) A simulated walking test refers to an in-vitro or bench test for axial fatigue of a peripheral scaffold according to the following protocol. A 6.0 mm inner diameter silicon tubing is axially stretched to 7% of its length and held in this position by attaching its ends to a first (fixed) member and a second, axially movable member of a frame. The second member is a linear actuator. The frame is programmed to axially cycle the silicon tubing back and forth between the stretched state and its original length; this will create a fixed axial percent compression strain to the intended test samples. The second or first member has an inner lumen in fluid communication with the stretched tubing lumen to allow passage of a scaffold-catheter into the lumen of the stretched tubing. The tube is submerged in a water bath filled with saline at 37 Deg. C. such that the testing condition is maintained at relevant environment. The length of the tubing used for the test depends on the length of the scaffold to be tested. The un-stretched tube has a length about twice the length of the scaffold. The scaffold is introduced into the lumen of the stretched-tubing via the second end lumen. The scaffold is introduced as a crimped scaffold on a FoxPlus 0.035 PTA catheter and advanced into the stretched tubing lumen. The PTA catheter has a 6.0 mm nominal inflation balloon. The scaffold, when positioned in the tube, is expanded to a post-dilation diameter of 6.5 mm. Balloon pressure is maintained for 2-5 min to minimize recoil and achieve apposition with the walls of the tube. The second member (coupled to a linear actuator) is programmed to move axially back and forth at a rate of 1 Hz (the length of the stroke is the length to return to the tubing in the un-stretched position) so as to apply an axially-cyclic compressive force. A three-month simulated walking test means 250,000 cycles of 7% compression at 1 Hz using the above test apparatus, wherein the cycles are applied over three consecutive days. A six-month simulated walking test means 500,000 cycles of 7% compression at 1 Hz using the above test apparatus, wherein the cycles are applied over six consecutive days.
VRT=A+B+A@B

(52) The metrics of functional output leading to VRT may be described generally in terms of the following A and B categories: A. Mechanical Modulation of the input site or the mechanical behavior of the scaffold after being implanted over time (hereinafter Input A to VRT); and B. Cellular conduction and inductionthe implanted scaffold's role as a tissue engineering (TE) template (hereinafter Input B to VRT).

(53) VRT then results from the combined effects, or convolution of A and B. The process is summarized in FIG. 24. These principles can apply to scaffolds made from a a biodegradable, bioabsorbable, bioresorbable, or bioerodable polymer and implanted into a coronary artery or peripheral artery. One of the important distinctions between the coronary and peripheral case, however, is the rate of change in mechanical properties of the peripheral scaffold following implantation changes as necessary for achieving VRT in a peripheral vessel. In both cases, however, the basic principles of VRT are the same, as will be appreciated.

(54) FIGS. 25A and 25B are plots showing, in general, the time-varying properties for a coronary verses a peripheral scaffold according to the disclosure. The plots show time-varying mechanical properties (Struc Discount), molecular weight (MW(t)) and mass (M(t)) of the scaffolds over a 12 month period following implantation in a coronary artery. FIG. 25B shows the time-varying properties for a peripheral scaffold over a 12 month period following implantation. There is a noticeable change in the scaffold's mechanical properties, e.g., its radial stiffness, as early as one month following implantation for the peripheral case, which may be thought of as a function of the number of developing strut discontinuities or fractures. The coronary scaffold, shown in FIG. 25A, by contrast, begins to breakdown not until much later in time, e.g., 4-6 months after implantation.

(55) VRT-related time constants, for coronary and peripheral scaffolds, are compared below:

(56) TABLE-US-00002 Coronary Peripheral VRT-Time constants (mos.) (mos.) Vessel scaffolding time 3 to 4 2 to 3 Scaffold threshold integrity retention Greater than, or 6 3 to 4 Scaffold stabilization by Neomedia/ 5 to 6 2 to 3 Neointimal growth Critical scaffold integrity loss Greater than, or 9 6 to 9 Time to total mass loss clinically irrelevant

(57) Noticeable changes in a coronary scaffold's mechanical properties are mostly attributed to a critical loss in molecular weight of the polymer composition forming the load bearing scaffold structure. The change in the peripheral scaffold mechanical properties is, in contrast, a response to the loading environment in which it is implanted. As FIG. 25B portrays, there is an almost immediate development of strut discontinuities following implantation, e.g., 7% of the scaffold struts fracturing one month from implantation. There is also a more rapid development of a neo-intima layer for the peripheral scaffold than the coronary scaffold. FIGS. 26A and 26B show similar plots for specific embodiments of a peripheral scaffold during the first three months following implantation.

(58) The loading on a coronary scaffold is mostly radial, reflecting the periodic contraction and expansion of blood vessels associated with blood flow through the vessels. The peripheral scaffold environment, however, is far more complex. FIGS. 27A and 27B show the types of movement and/or loading of a superficial femoral artery (SFA) of the leg. The vessel undergoes significant torsion, bending, axial contraction and extension and compression (crushing/pinching). For scaffolds implanted within this region, especially when the scaffolds are over about 40 mm in length, it is inevitable that fractures and breakdown of the scaffold begin to occur within the first month, or even within the first 1-2 weeks following implantation. In accordance with the disclosure, this process of breakdown of the scaffold's load bearing structure in a peripheral vessel, e.g., the SFA, however, can be controlled so that the supporting function of the scaffold is provided for only long enough that a neointimal layer has developed and the vessel has been restored to a state where structural support of the scaffold is no longer essential to proper vascular function. Indeed, a controlled reduction in mechanical properties (brought about by the breakdown of the scaffold structure) is believed more beneficial to restoring a more natural vascular function than, e.g., a scaffold or stent that retains its mechanical supporting properties beyond that needed to support the vessel. After the vessel has begun to repair itself, a scaffold that remains relatively radially and/or axial stiff is believed an impediment to the healing process. Thus, in accordance with the disclosure the controlled development of strut discontinuities in a scaffold is believed a necessary condition for Input A to VRT.

(59) The design and mechanical properties of a peripheral scaffold supporting the VRT objective, i.e., Input A to VRT, will now be discussed in greater detail. This general discussion is then followed specific examples of time-varying attributes of preferred scaffold designs.

(60) Input A to VRT: Mechanical Modulation of the Implant Site as a Function of Time.

(61) 1) Bioresorbable Design Metric:

(62) i. The M Parameter

(63) The M parameter refers generally to the scaffold's geometry and behavior resulting from that geometry. That is, the number of crowns, linking elements, number of crowns, the angles between crowns, the wall thickness, etc. Thus, an M parameter refers to such things as the height, width, thickness of struts and crowns, number of crowns, number of rings, outer diameter, and wall thickness. This category therefore defines the idealized flexural rigidity of struts, hoop strength/stiffness, radial strength (as defined in WO2011094621), radial stiffness, and related structural mechanics for the scaffold given the material used and dimensions of the load-bearing and interconnected elements. Tables 1-2 and FIG. 6A provide examples of some or all of the features from which an M parameter, which is a number, may be based.

(64) ii. Polymer Selection and Degradation Profile.

(65) This aspect of the design input refers to the choice of material, and its sequence of polymer-molecular weight, strength and mass reduction over time, see e.g., Middleton John C, et al Synthetic biodegradable polymers as orthopedic devices (Biomaterials 21 (2000) 2335-2346) (FIG. 10), for the particular polymer or polymer blend used to form the backbone or scaffold of the load-bearing bioresorbable structure. As noted above, for a coronary scaffold the point in time when there is critical loss in molecular weight signals the time when there is a reduction in mechanical properties of the scaffold, e.g., radial stiffness. This phenomenon typically begins to occur within 4-6 months following implantation. For a peripheral scaffold according to the disclosure the loading environment and design produces a reduction in mechanical properties far sooner. As such, according to embodiments disclosed the peripheral scaffold loses most of its radial support capability well before the 4-6 months period followed implantation.

(66) iii. Scaffold Processing History; Temperature and Force Profile Over Time, Exposure to Moisture, Gas, and Energy.

(67) This aspect of design refers to the processes used to arrive at an implantable medical device. Unlike a metal stent, the processing conditions for forming a polymer tube from which a scaffold is made can greatly affects properties such as its lowest crimping profile, deployment profile, and radial strength/stiffness. In a preferred embodiment the scaffolding is formed from a tube cut to form the scaffold's network of interconnected struts and linking elements. A process for forming the tube is described in U.S. patent application Ser. No. 12/558,105. The processing parameters include extrusion then biaxial expansion of a tube within a prescribed temperature range to increase the radial strength of the tube while maintaining a desired amount fracture toughness in the expanded tube. After forming the scaffold, it is then crimped to a balloon. The crimped scaffold is then sterilized, either by a gas or by E-beam radiation. The scaffold is plastically deformed from its crimped state when implanted within a vessel. Additional effects of the processing condition include the pre-crimp, crimped and deployment diameters (all of which can be different from each other), and recoil of the scaffold after being implanted within the vessel.

(68) 2) Functional Output Metric

(69) 1. Flexible Navigation Through the Vessel and Easy Deployment.

(70) The crossing profile of the crimped scaffold and manner in which the scaffold was crimped influences this functional output. It has been found that a bioresorbable, balloon-expanded PLLA scaffold is particularly sensitive to the crimping process. The crimping process can affect not only the structural integrity of the crimped scaffold, but also its ability to deploy uniformly. If deployed non-uniformly or with significant crack propagation (as a result of the crimping process) then several stress concentrations can develop, which can cause premature failure or strut discontinuities.

(71) The ability to flexibly navigate through a vessel also requires a sufficient retention force on the scaffold, to prevent it from becoming dislodged. However, for a peripherally-implanted scaffold this is sometimes not an issue since the scaffold is significantly longer than a coronary scaffold.

(72) 2. Radial/Pinch Strength and Stiffness at t=0

(73) I. Pre-Implant (Scaffold-Only)

(74) II. Immediate Post-Implant (Implanted Segment In Vivo)

(75) As discussed in greater detail, below, the pre-implant stiffness can vary greatly from the as-fabricated, or as crimped stiffness. The effects on the scaffold's stiffness at the time of implantation can be reduced significantly due to such combined effects as sterilization and shelve life, either of which can cause the radial stiffness/strength to decrease and/or its brittleness in increase. Immediately following implantation, however, the stiffness/strength can increase dramatically, e.g., double, as a result of hydration within the vessel.

(76) 3. Rate of Decrease in Radial Strength, Radial and Stiffness, Pinch Strength, Pinch Stiffness, or Crush Energy as a Function of Time In Vivo.

(77) It is desirable to design a bioresorbable scaffold with a controlled initial increase followed by a gradual decrease in scaffolding property such as radial strength, radial stiffness, pinch strength, pinch stiffness, or crush energy as a function of time and its integration into the vessel wall. The functional form of this stiffness variation over time, i.e., f(t), is described in greater detail below. The initial increase in strength/stiffness allows the design of the implant to be less rigid and low modulus pre-implant, while successfully creating patency within occlusive strictures by scaffolding at higher radial strength/stiffness for the initial time period, i.e., within the first 10 days following implant.

(78) As discussed in greater detail below, optimal strength and stiffness, and optimal rate of decrease in strength and stiffness reflects a balance between strength and ductility or resistance to excessive discontinuities, while at the same time achieving a gradual decrease in strength/stiffness/crush energy over time (by way of discontinuities or fractures in the scaffold structure, including struts forming rings and linking elements). In one particular preferred embodiment, e.g., V80, the stiffness and strength at t=0 is significantly lower than prior designs for purposes achieving the optimal rate of change in stiffness over the period of about 0-3 months. Examples of scaffold structural characteristics having a direct influence on the M parameter for V80 at t=0 are provided in FIGS. 4, 5A and 6A, and TABLE 2 and 4.

(79) 3) Design and Function in Relation to VRT Goals

(80) The design and functional metrics of the scaffold then provide the following favorable qualities for VRT: (1) decrease in average forces to the vessel (e.g. vessel geometry re-structuring, outward radial force); and (2) decrease in resistance to Fluctuation forces derived from vessel tonicity and pulsatility (e.g., compliance mismatch with native vessel).

(81) As the scaffold's radial stiffness (primarily) decreases over time (as a result of fracturing struts) its force influence on the healing vessel tissue concomitantly decreases. This re-balancing over forces between vessel and scaffold is believed favorable and better promotes healing than the case where the scaffold radial stiffness more or less stays the same over this time period, such as in the case of non-bioresorbable metal stent (FIG. 25).

(82) The change in mechanical properties resulting from the fracturing structure also provides the additional benefit of causing the combined structural dynamics of the vessel and implanted scaffold to converge towards that of the native vessel (as the vessel heals). Thus, as the scaffold becomes more compliant, or as the inter-ring forces of the scaffold become more and more de-coupled from each other, the vessel is permitted to return to a harmonic motion (as blood rushes through the vessel) so that it becomes more like that of neighboring native vessel segments. The scaffold's ability to drive or influence the natural harmonic motion of the vessel gradually decreases as the structural integrity of the vessel improves.

(83) 4) Analytic Modeling of Decrease in Stiffness Over Time (Exponential Decay) as a Design Input Parameter

(84) The approach taken to model and design the scaffold to achieve the foregoing benefits may begin with defining time constants defining the initial rise in stiffness/strength following implantation and the decay period, from the time of greatest strength/stiffness to the value for strength and stiffness that the scaffold will eventually after a predetermined period, e.g., 3 months. A first criterion is a safety-related criterion, which requires that the time period from implantation until critical scaffold integrity loss, e.g., of radial strength or stiffness loss is greater than the time period needed to achieve tissue stability. Or, in terms of a time constants,
K.sub.B>K.sub.A

(85) Where K.sub.B is the rate constant of neointimal formation and K.sub.A is the rate constant for critical scaffold disintegration. The criterion is enforced on the design for the purpose of minimizing chances that an embolization could occur within a vessel due to excessive strut discontinuities occurring before a neointimal layer has sufficiently developed over the scaffold body. Thus, the design (M parameter, etc.) needs to take into consideration avoidance of host-material interaction resulting in adverse safety events occurring during the absorption process.

(86) EQ. D1 is used to represent the characteristics of the scaffold's time rate of change in stiffness/strength (as a ratio of a starting value) as an indicator of the scaffolded vessel's response to an applied load.
S(t)/S.sub.O=S.sub.OV/S.sub.O+(1S.sub.OV/S.sub.OC)e.sup.t/k+Ce.sup.t/Ko,(EQ. D1)

(87) where S(t)/Sov=(S(t)/So)*(So/Sov)

(88) S(t=0)/So=1

(89) Examples of plots of EQ. D1 for specific scaffold designs are reproduced as FIGS. 26A-26B. TABLES 1.1-1.5 and the accompanying discussion below further disclose a method for representing the time-varying pinching stiffness for scaffolds, utilizing explant pinching stiffness data, in terms of EQ. D1. This relationship of the coefficients to physical quantities and their constitutive relationships to other equations follow. So can be the radial strength, radial stiffness, crush strength or crush stiffness of scaffold at t=0; So=g(Xi design, Xi mat, Xi process); So=g(M) for a given process and materials Variable set (Xi design) depends on M parameter. As mentioned earlier, So also depends on crimping process, time lapse after sterilization, sterilization and other processes, in addition to the M parameter. Sov is the radial strength/stiffness or crush strength/stiffness of the reference vessel; S(t) is the radial strength/stiffness or crush strength/stiffness of the scaffold, e.g. t=0 . . . 3 months; K=f(Xi design, Xi mat, Xi process); K=f(M) for a given process and materials; where M refers to the M parameter reflecting the decrease in scaffold properties as struts fracture; and C, Ko=g(Xi design, Xi mat, Xi process); KO, C=g(Mo) where Mo refers to an M parameter reflecting the initial rise properties of the scaffold after implantation.

(90) The Xi (design, material and process for making the scaffold) refer to the variables (discussed earlier) in design affecting the value of K, Ko, C. K is the time constant for occurrence of strut discontent, a longer time phenomena; C and Ko describes the intensity and time constant respectively for the stiffness/strength rise, a shorter time phenomena. Therefore Ko<<K in EQ. D1. Value of C determines how much initial stiffness occurs. Ko and C characterize the initial stiffness/strength rises upon implantation due to wetting, plasticization, and polymer chain orientation. This is a short time-constant phenomena starting from right after implant and completing by 2-3 days, one week or two weeks. Therefore Ko is always much smaller than K.

(91) EQ. D1 was derived from the hypothesis that the time rate of range of the difference between a scaffold's stiffness S(t) and native or diseased vessel stiffness Soy, d(SSov)/dt can be approximated as follows:
d(SSov)/dt=R*f(t)M*(SSov).sup.nEQ. D2

(92) Where f(t) is a general function of time. Based on observed explants of scaffold the exponential form was believed to be a good choice for f(t) and n=1 a good approximation for the power. R is a factor accounting for the observed increase in radial strength and stiffness of the scaffold that had occurred during the first two-weeks following implantation. This increase in stiffness is due to hydration of the polymer material, as discussed above. The same effects have been seen in bench tests. Page 3 of APPENDIX I (U.S. Provisional Application Ser. No. 61/717,613) shows scaffold work done (N*mm) on explants from animal data for the V59 scaffold for shortly after implantation, and one week and two weeks after implantation. The V59 control shows the value for a scaffold prior to implantation. As can been seen in these plots, there is a significant rise. This is the R term. Pages 1, 2, and 4-6 show similar results for stiffness for bench testing for the V80 (described in detail below) and the V59.

(93) Page 1 of APPENDIX I shows an increase in both radial strength and K-Lnorm after 3 days submerged in water at 37 C. and after undergoing 250 k cycles of axial loading of between 7% axial compression of the scaffold (as a percentage of the scaffold total length). There were about 10% observed strut fractures from scaffolds that had gone through 250 cycles of axial fatigue testing (3-month simulated walking).

(94) Page 3 of APPENDIX I (ex-vivo flat plate testing data done w/V59 scaffolds implanted w/in vessels) indicates a minimal difference between V59 0d (scaffolds inside arteries) vs. V59 Control (scaffolds only, no artery present). After 7 days post implant, an increasing of >35% in crush recovery energy (N*mm) was observed when compared to V59 0d (13.5 N*mm vs. 10.0 N*mm).

(95) Pages 4-5 of APPENDIX I show an increasing of up to about 100% in radial strength of 3-month aged V79 and V80 devices (crimped onto 2 different balloon catheters 0.018 vs. 0.035) post 6 days of hydration from 500,000 cycles of axial fatigue (six-month simulated walking test). These graphs show the variation in increased strength/stiffness depending on the amount of crimping that was done from an initial crimp size).

(96) Referring again to EQ. D2 the M is the M parameter discussed earlier. It is a constant value determined from the design, materials, fabrication process, etc. as discussed above. Thus, there is some unique value, called the M parameter for the scaffolds V79, V80, etc. that is used solely for convenience, so that d(SSov)/dt may be expressed in a convenient and more intuitive form reflecting observations during test.

(97) Similarly, the scaffold stiffness prior to implantation, or So and the time constants K, Ko may be expressed in terms of an M parameter, or Mo parameter (where Mo reflects the properties of the scaffold that gives it the initial rise within the about two weeks following implantation (and prior to the onset of fractures) as opposed to later-stage stiffness/strength properties represented by M). Again the concept of M parameter of Mo parameter is a value unique to every scaffold and based on its design, material, etc. From this representation of the problem the C in the equation above is equal to R/So (MMo), where C is a factor associated with the initial rise in strength/stiffness.

(98) Coefficient values and ranges for embodiments of EQ. D1 have been estimated for the V59, V79, and V80 scaffolds. These coefficient values are given in TABLE 1A, along with ranges of these coefficients for other embodiments of a peripheral scaffold according to the disclosure. Utilizing EQ. D1 and these coefficients time varying peripheral scaffold properties may be estimated, preferably over the first 6 months following implantation, more preferably 3 months following implantation, and more preferably within the first month, or on or about 7, 28, 60, 90 and/or 180 days after implantation.

(99) With reference to TABLES 1.1-1.5, below, the following describes a process for estimating a rate of change of a mechanical property over a period of 7 to 90 days following implantation. The objective is twofold.

(100) First, one wants to utilize extensive explant data over the 7 to 90 day time period (in the example below, the V59 scaffold) to estimate changes in mechanical properties for similar scaffolds (in the example below, the V79 and V80 scaffolds). The scaffolds are said to be similar based on an understanding of mechanical properties and testing (in-vitro) to enable one to reasonably account for differences (see FIGS. 7-23 showing testing).

(101) Second, one wants to arrive at ranges for the coefficients in EQ. D1 based on the knowledge gained from the differences between key coefficients affecting the first and second exponential decay terms in EQ. D1 based differences between the scaffolds, e.g., differences between the V59, V79 and V80, in combination with the differences in the scaffold properties. From this comparison, a design tool can be used for Input A to VRT that provides the time-varying metric to a scaffold design process.

(102) Estimates for time-varying pinching stiffness properties for the V79 and V80 scaffold, based on in-vitro data and limited in-vivo data (7 and 28 days) for these scaffold, and more extensive in vivo today for V59 (7 to 90 days) may be determined in the following manner.

(103) In the following example, percentile fracture is known for V59, V79 and V80 for 0, 7 and 28 days after implantation in an animal model. Also, a ratio of pinching stiffness S/SO for V59 explants from the animal model is known for 0, 7 and 28 days (as well 14, 28, 90, 180 and 265 days, see TABLE 1.1). S/SO is only known for 0 and 7 days for V79 and V80. However, based on in-vitro tests of V79, V80 it is believed that for time intervals of 1, 2, and in some cases 3 months from implantation the percentage fracture in combination with the in-vitro data (e.g., simulated walking test) and material properties (e.g., stiffness, strength, toughness, etc.) can be utilized to provide reasonably accurate estimates of S/SO, e.g., ratio of pinching stiffness for an explant, to the extent that a working model of time-varying mechanical properties can be formulated to assess a scaffold's fitness for use prior to in-vivo validation.

(104) The first step is to calculate a slope for ln (S0/S) verses ln(1d) for the V59, where ln(SO/S) is the natural log of the pre-implant pinch stiffness over the post-implant pinch stiffness for the V59 and ln(1d) is the natural log of the number of intact struts found in the V59 explant (d=is the number of discontinuous struts, as a percentage of the total). It can be shown that this slope is 1.24 for the V59. Using this slope, EQ. B1 is used to estimate S/SO for later time points (as a function of the percentage of discontinuous struts).
S/S0=S7/S0*((1d)/(1d7)).sup.1.24(EQ. B1)

(105) The data in TABLE 1.1 indicates that the EQ. B1 provides good estimates (col. 6) of the actual S/SO values (col. 3) for the V59. Based on this conclusion, EQ. B1 is then used to estimate S/SO for V79 and V80 at 7 and 28 days from implant. These estimates are provided in col. 5 of TABLE 1.2.

(106) TABLE-US-00003 TABLE 1.1 % stiffness Validation of time, discount. ratio measured values days struts (S/SO) Ln s/s0 Ln (1 d) using EQ. B.1 0 0 1.00 0 0 7 7.28 1.15 0.14 0.08 1.15 14 20.60 .931 0.07 0.23 0.95 28 39.20 .742 0.30 0.50 0.68 90 54.00 .481 0.73 0.78 0.48 180 57.00 .197 1.62 0.84 0.44 365 76.00 .065 2.74 1.43 0.21

(107) TABLE-US-00004 TABLE 1.2 % discont. % discont. S7/S0 (7 EQ. B1 struts at struts at day pinch estimates 28 days from 7 days from stiffness of S/SO at explants explants ratio) 28 days V59 40 7.28 1.15 0.68 V79 13 0.00 1.30** 1.09 V80 7 0.00 1.30** 1.19 **1.3 for S/SO at 7 days is derived from the in-vitro data, which is believed a good estimate given no discontinuous struts found in V79, V80 explants after 7 days.

(108) Next, coefficients for EQ. D1 are estimated for the V59, V79 and V80 scaffolds, as well as a range for a SCAFFOLD 1 type and SCAFFOLD 2 type. The coefficients are shown in TABLE 1.3.

(109) The coefficients for time-varying properties governed by EQ. D1 for embodiment SCAFFOLD1 and SCAFFOLD2 are based on the differences in the M parameters, e.g., struts, crowns, links, between V59, V79 and V80, the longer term V59 explant data, simulated walking tests and measured static properties from the in-vitro tests for V2, V23, V59, V79, V80, V62, and V78. SCAFFOLD1 has a backbone structure similar to V80, but with M parameter variations (e.g., ratio of diameter to wall thickness, strut width to thickness ratio, crown angles and radius and/or processing parameters such as biaxial expansion in radial and axial direction taken into consideration). SCAFFOLD2 is similar to the range of scaffolds studied in TABLE 3, but with M parameter variations taken into consideration for these scaffolds. See TABLES 3-4 below, FIGS. 7-23, APPENDIX I and accompanying discussion below.

(110) TABLE-US-00005 TABLE 1.3 Coeff. V59-ex V80-ex V79-ex (EQ. D1) Units vivo vivo est. vivo est. SCAFFOLD1 SCAFFOLD2 R/S0 (1/day) 0.40 0.51 0.57 0.45-0.6 0.45-2.5 Ko day 0.65 0.65 0.65 0.66-2.0 0.66-7.0 K day 60.00 250.00 125.00 200-375 70-1000 c ratio 0.26 0.33 0.37 (0.3) to (1.2) (0.275) to (2.5) S0/S0-.sub.V59 S0 ratio, 1.00 0.50 1.00 0.35-0.75 0.25-0.95; or with respect 1.1-2.0 to V-59

(111) Embodiments contemplated include scaffolds having time-varying mechanical properties satisfying EQ. D1 over ranges of 1 month, 2, months, and 3 months from implantation.

(112) The coefficients generated above, when used with EQ. D1 produce the estimates of in-vivo pinch stiffness ratios provided below as TABLE 1.4. The columns 2-4 show the predicted S/SO for each scaffold using EQ. D1 and column 5 provides the measured S/SO from the V59 explant data.

(113) TABLE-US-00006 TABLE 1.4 values for S/SO for V59, V79, V80 using EQ. D1 and compared to V59 explant data (S = pinching stiffness at time t; S0 = pinching stiffness at time of implant) V59 days V79 S/S0 V59 S/S0 V80 S/S0 explant 0 1.00 1.00 1.00 3 1.34 1.20 1.31 7 1.30 1.12 1.30 1.15 12 1.25 1.04 1.27 14 1.23 1.00 1.26 0.93 21 1.16 0.89 1.23 28 1.10 0.80 1.19 0.74 35 1.04 0.71 1.16 42 0.98 0.63 1.13 52 0.91 0.54 1.09 60 0.85 0.47 1.05 75 0.76 0.37 0.99 90 0.67 0.29 0.94 0.48 105 0.60 0.23 0.88 120 0.53 0.18 0.83 150 0.42 0.11 0.74 180 0.33 0.07 0.66 0.20 210 0.26 0.05 0.59 240 0.21 0.03 0.52 270 0.17 0.02 0.47 310 0.12 0.02 0.40 360 0.09 0.01 0.33 0.06

(114) The values for So depend on the time spent between initial fabrication and assembly of the scaffold and catheter and when it is implanted. S(t) above represents the ranges of increase in radial stiffness expected for the scaffold, corresponding to the time constant Ko.

(115) After implantation tests and in-vivo data show that scaffold properties such as stiffness can increase to about 1.3 or more times a pre-implant value, as shown, e.g., in TABLE 1.4 and other tests. After this period of time, developing fractures cause the stiffness to decrease. This is represented in the examples of FIGS. 26A-26B and TABLE 1.4 above as well.

(116) This initial rise in both radial and crush strength/stiffness is expressed by the second exponential term Ce.sup.t/Ko in EQ. D1. It is a function Ko (time constant for the initial rise). Since the initial rise occurs only over a relatively short time, Ko<<K.

(117) A decay in both crush and radial strength/stiffness, which is attributed to fractures developing in the scaffold, is represented by the second exponential term (1S.sub.OV/S.sub.OC)e.sup.t/k in EQ. D1. As can be seen in the curves, EQ. D1 fits well to the V59 in vivo data.

(118) Slope for S(t)/S.sub.o
d(S(t)/S.sub.o)/dt=1/k(1S.sub.OV/S.sub.OC)e.sup.t/kC/Ko e.sup.t/Ko(EQ. D3)
Curvature for S/S.sub.o
d.sup.2(S(t)/S.sub.o)/dt.sup.2=1/k.sup.2(1S.sub.OV/S.sub.OC)e.sup.t/k+C/Ko.sup.2e.sup.t/Ko(EQ. D4)

(119) The slope is negative, but the curvature is positive, which is what is seen in the in vivo data. After an initial increase in fracture and concomitant loss in radial strength/stiffness the strength and/or stiffness begin to converge to a constant value. Moreover, this convergence occurs well before there begins a significant loss in molecular weight of the bioresorbable polymer. This phenomenon may be understood from the following. After a certain number of struts/links have fracture, the remaining intact structure has less forces applied to it. The structure becomes much weaker, but settles to stiffness and strength values sufficient for purposes of VRT. The vessel after a certain time period has healed and does not need the scaffolding for supporting the walls. The scaffold has done its purpose and is not needed any longer as the primary load-bearing member.

(120) TABLE 1.5 shows slopes for V59, V79 and V80 using EQ. D3. The values in TABLE 1.5 are the computed slopes multiplied by a factor 100. Thus, for example, the slope or rate of change in S/SO at day 7 for the V80 is 0.5110.sup.2/days. As indicated, there is an initial sharp rise in the slope, followed by a gradual decrease.

(121) TABLE-US-00007 TABLE 1.5 Values for EQ. D3 for V59, V79 and V80 (100 * d(S(t)/S.sub.o)/dt) t, days V79 V59 V80 0 56.21 38.35 50.61 3 0.50 1.59 0.01 7 1.03 1.86 0.51 12 0.99 1.71 0.50 14 0.97 1.65 0.50 21 0.92 1.47 0.48 28 0.87 1.31 0.47 35 0.82 1.17 0.46 42 0.78 1.04 0.44 52 0.72 0.88 0.43 60 0.67 0.77 0.41 75 0.60 0.60 0.39 90 0.53 0.47 0.37 105 0.47 0.36 0.34 120 0.42 0.28 0.32 150 0.33 0.17 0.29 180 0.26 0.10 0.26 210 0.20 0.06 0.23 240 0.16 0.04 0.20 270 0.13 0.02 0.18 310 0.09 0.01 0.15 360 0.06 0.01 0.12 450 0.03 0.00 0.09 540 0.01 0.00 0.06 730 0.00 0.00 0.03

(122) Based on the foregoing, in some embodiments, a slope or rate of change in a mechanical property (100) with respect to time over the interval of greater than about 7 days and up to 3 months from implantation may range from about 1 to 0.37, more narrowly, about 0.5 to 0.3, and about 0.8 to 0.2. In some embodiments, the slope may be, for between 7-28 days between about 0.55 and 0.45, and 1 to 0.8. The slope may be, in some embodiments, for between 28 and 60 days between about 0.45 and 0.35, or 0.55 to 0.35. It is understood that these slope ranges at both endpoints are divided by 100. Moreover, all of the above slope value ranges may be present in a scaffold structure made from a polymer composition comprising PLLA, have rings connected by link elements and a ring may have been 8 to 12 crowns, 8 crowns, 12 crowns, and at most 2 links, or at most 3 links. All of the foregoing slopes, of the range of 1-3 months, 1 month, 2 months, or a slope over a day (as provided above) are within the scope of the invention.

(123) FIGS. 1 through 6B and the discussion below describe the M parameter elements pertaining to the scaffolds in TABLE 2.

(124) TABLE-US-00008 TABLE 2 Input A to VRT parameters (pre-implant) V59 V76 V79 V80 Outer diameter 8 mm 7 mm 7 mm 7 mm (mm) Wall thickness .011 in .011 in .011 in .011 in (in) Crush recovery See See See See TABLE TABLE TABLE TABLE 3B 3B 3B 3B K-norm (N/mm) 8*(1.24) = 7*(1.64) = 7*(1.46) = 7*(1.09) = (FIG. 23) 9.92 11.48 10.22 7.62 Radial Strength .65 .93 .78 .55 (N/mm) In-vivo percent 28-38 11 13 8 strut fractures (28 days) Number of 8 8 8 12 crowns per ring Number of links 4 3 3 2 connecting rings Scaffold PLLA PLLA PLLA PLLA material Scaffold Biaxial expansion of PLLA extruded tube (processing fabrication conditions and resulting morphology as described U.S. process application Ser. No. 13/840,257 which is cut into scaffold pattern using laser parameters as described in Table 2 of US20120073733. Scaffold - Crimp scaffold to 2.03 mm outer diameter using the catheter process described on FIG. 3A of U.S. application assembly Ser. No. 13/644,347. Scaffolds crimped to 6.0 mm balloon. Scaffold-catheter assemblies are then sterilized using E-beam radiation. Scaffold Scaffolds deployed to about 6.5 mm outer diameter deployment within an about 6.0 reference vessel diameter (in-vivo) or 6.4 tube (in-vitro).

(125) The time interval most critical to a peripheral scaffold's ability to provide a structural property to the vessel, for purposes of VRT, is the first three months following implantation. It is preferred to have a gradual drop in a mechanical property of the scaffold following implantation, such that after 28 days the scaffold has retained about the same mechanical properties it had proper to implantation.

(126) B. Cellular Conduction and Induction Phenomena Responding to a Tissue Engineering (TE) Template.

(127) Input Type B to VRT is now discussed. The Type B input to VRT refers to B=Cellular conduction and induction phenomena responding to a Tissue engineering (TE) template. The bioabsorbable scaffold acts as a TE template. Metrics for the Type B input to VRT include: High scaffold surface to volume (S/V) ratio varies with increased strut discontinuity provides a TE template. Therefore, the S/V ratio is a f(t). Evolution of texture during degradation provides a TE template. Thus, a roughness of the scaffold surfaces is a f(t). Degradation product of PLLA scaffoldLactic acid and PLA low MW entity. These by-products of the degradation product have an inductive effect on tissue ingrowth and healing. Therefore, the distribution of MW(t) and Lactic acid is a f(t).

(128) (the phrase as/is a f(t) throughout the disclosure means as/is a function of time). Specific embodiments include a V62, V79, V76, V78 or V80 scaffold having a 7 mm as-cut or as-fabricated outer tube diameter, wall thickness of 0.011 in, between 8-12 crowns, 2 link elements between rings, and a length of 35 to 38 mm.

(129) A metric of Vascular Restorative Therapy is cellular conduction and induction phenomena responding to the bioabsorbable scaffold which acts as a Tissue engineering (TE) template. In general, tissue engineering is the science of persuading living systems to regenerate or repair tissues that fail to heal spontaneously. In one approach, a template that supports and guides the generation of new tissue is implanted into a living system to facilitate tissue repair. Tissue engineering templates use a combination of engineering design and material selection to create performance-driven components that guide the generation of new tissue.

(130) In the case of a bioabsorbable vascular scaffold, endothelial and smooth muscle cells grow over the scaffold body after implantation. This process is usually referred to as endothelialization. Endothelialization is an important part of the healing process with a bioabsorbable scaffold. Endothelialization refers to coverage of a surface with endothelial tissue or endothelial cells. Through this process, the scaffold can become embedded within an endothelial layer and smooth muscle cells. At later stages, significant mass loss occurs resulting in complete absorption of the scaffold.

(131) An implanted bioabsorbable scaffold has a time dependent behavior and biological response. This is described in detail in US2011/0066223, US2011/0066225 and US2010/0198331, which show a decrease in radial strength beginning at about three months after a scaffold is implanted. The scaffold depicted is assumed to not develop any significant fracturing that would affect the radial strength, or otherwise have a change to its radial strength until about three months after implantation. This is the case for certain types of implanted bioresorbable scaffolds, such as coronary scaffolds. For a peripherally implanted scaffold, however, the radial strength does change significantly and well before the three month period has passed, due to the onset of significant fracturing in ring struts relatively earlier into the patency period. The preceding analysis utilizing EQ. D1 and the explant data demonstrate this breakdown process.

(132) Generally speaking, upon implantation the molecular weight of the polymer of the scaffold decreases due to chemical degradation which eventually leads to a decrease in strength of the polymer. The decrease in polymer strength contributes to a decrease in radial strength of the scaffold. Scaffold integrity loss also occurs in the form of strut discontinuities, or fractures. Strut discontinuities may occur at the links in the scaffold resulting in partial or complete decoupling of the rings of the scaffold. Such link discontinuities can result in little or no loss in radial strength.

(133) Therefore, without being limited by theory, the decrease in radial strength for an implanted peripheral bioabsorbable polymer scaffold can be due to two contributions: (1) decrease in the polymer strength arising from molecular weight decrease from degradation (2) fracture or discontinuities in the scaffold struts. Contribution (1) tends to cause a rather abrupt drop in radial strength, although timing of that change depends heavily on the polymer molecular structure and morphology (e.g., around 3 months post-implantationsee FIG. 5B of Exhibit G). The data disclosed herein suggest that contribution (2) tends to cause a gradual decrease in the radial strength with time starting within a few weeks post-implantation. It is believed that the rate of fracturing initially increases then decreases until no further fracturing occurs, since the radial strength appears to approach or reach a steady state value. It is further believed that a scaffold can be designed such that the contributions that can be manipulated to achieve a desired radial strength profile.

(134) The radial strength decrease as a result in loss of molecule weight usually occurs only after a sustained period of patency (usually at least 3 months, pending the molecular structure and morphology) which allows for positive remodeling of the vessel wall. Thus, after the period of sustained patency, the vessel wall can maintain an increased mean lumen diameter, as shown by the mean lumen diameter.

(135) Morphologically and functionally competent neointima/neomedia of the endothelial layer stabilizes scaffold and reduces thrombosis risk. Time for tissue stabilization is 4-5 months and for integrity loss is 6-9 months.

(136) Controlled and gradual reduction of scaffolding strength and stiffness as function of time of the scaffold results in: reduction in compliance mismatch between the scaffold and native vessel with increased endoluminal deformability, an independent load-bearing integrated composite of the scaffold and native vessel (range of data cited1.5 wk to 9 months), plaque fibrocellular capping and volume reduction (exhibit H).

(137) With regard to plaque, the vessel wall includes a plaque region including a necrotic core component and a fibrocellular or fibrous component. As the scaffold degrades the fibrous component becomes positioned between the necrotic core component and the blood-contacting surface of the vessel wall so that the necrotic core component is not in contact with the blood-contacting surface, i.e., the necrotic core is capped by the fibrous component. There is also a reduction in volume of necrotic component as the scaffold degrades.

(138) There are several possible metrics for cellular conduction and induction phenomena.

(139) The first metric is the surface to volume (S/V) ratio of the scaffold. In general, it is believed that the S/V ratio of the scaffold influences the cellular growth over the scaffold. Specifically, it is believed that a high S/V favors cell deposition and growth on the scaffold. The surface can refer to the luminal surface, abluminal surface, side wall surfaces, or any combination thereof. It is further believed that the increase in S/V ratio generated due by strut discontinuities provides additional TE template and enhances or increases cell attachment and growth. When strut discontinuities are generated additional surface area is created at the discontinuities, which increases the S/V ratio. The number of strut discontinuities change with time, so the S/V metric is time dependent. The discontinuities at the links will enhance cell attachment and growth during the first three months after implantation while the scaffold provides patency. The discontinuities in the rings will further increase cell attachment and growth.

(140) The volume of the scaffold changes with time also due to mass loss. The decrease in the volume as the scaffold degrades further contributes to the time dependence of the S/V metric.

(141) Additionally, the S/V ratio with the bulk of the scaffold also changes with time. As a bulk-eroding polymer erodes, mass loss occurs throughout the volume of the scaffold which creates voids or pores throughout the volume of the scaffold. Therefore, the porosity of the scaffold increases with time, which increases the S/V ratio of the scaffold. The surface area within the scaffold provides a TE template for cell growth and attachment.

(142) Another metric for cellular growth is the roughness of the scaffold surface. As the scaffold degrades, texture or roughness evolves on the stent surface due to mass loss. The evolution of this texture during degradation provides additional TE template. It is believed that the increase in surface area provided by such texture or roughness enhances cellular attachment and growth. Therefore, the roughness factor of the scaffold surface as a function of time is a metric for cellular growth.

(143) An additional metric for cellular growth is the generation of degradation by products of the biodegradable polymer, such as PLLA. Specifically, degradation by products of a PLLA scaffold include low MW PLLA and lactic acid of the PLLA scaffold. Lactic acid and low MW PLLA have an inductive effect on tissue ingrowth and healing. Therefore distribution of MW(t) and lactic acid and low MW PLLA as a function of time are a metric.

(144) The mechanical modulation and cellular conduction metrics of the disclosed scaffolds can facilitate clinically beneficial outcomes in the treatment of refractory lesions, bifurcated lesions, treatment of chronic total occlusion (CTO), vulnerable plaque (VP), left main, angulation, ostial, and multi-vessel treatment. Refractory lesions are typical in diabetic patients. Specifically, beneficial outcomes are facilitated by the gradual reduction in compliance mismatch with the vessel and the scaffold and reduction in chronic outward force with time. Additionally, beneficial outcomes are facilitated by the increase in cellular growth due to the increase in S/V, increase in roughness and induction in cell growth by degradation by-products. Further, beneficial outcomes are facilitated by capping of necrotic core plaque by fibrous plaque.

(145) More specific examples of scaffolds, processes for making, fabricating and assembly the same, and observed outcomes (both in vivo and ex vivo) further explaining VRT principles and objectives follow.

(146) Embodiments of processes for forming a deformed polymer tube from a precursor are provided. According to the disclosure, a crush recoverable and balloon expandable scaffold having time-varying properties is cut from a tube (FIG. 1) formed through a process intended to enhance mechanical properties of the scaffold including fracture toughness. Discussion of the scaffold patterns according to several embodiments are discussed next. Examples of the scaffold patterns are provided. During this discussion, reference is made to aspects of a scaffold found to play an important role in the stiffness, strength, crimping and deployment of a polymer scaffold. Finally, bench and in-vivo test results are discussed, including exemplary examples of embodiments of invention and explanation of the results observed and problems overcome. In these examples there may be gained a further appreciation of aspects of inventiona balloon-expandable polymer scaffold having time-varying properties for purposes of achieving a desired Input A to the VRT processand examples of processes including sample M parameters for predicting, assessing and improving upon a scaffold's fitness for use in a peripheral vessel.

(147) The polymer scaffold illustrated in FIG. 2 is formed from a poly(L-lactide) (PLLA) tube. The process for forming this PLLA tube may be the process described in U.S. patent application Ser. No. 12/558,105. Reference is made to a precursor that is deformed in order to produce the tube of FIG. 1 having the desired scaffold diameter, thickness and material properties as set forth below. Before the tube is deformed or, in some embodiments, expanded to produce the desired properties in the starting tube for the scaffold, the precursor is formed. The precursor may be formed by an extrusion process which starts with raw PLLA resin material heated above the melt temperature of the polymer which is then extruded through a die. Then, in one example, an expansion process for forming an expanded PLLA tube includes heating a PLLA precursor above the PLLA glass transition temperature (i.e., 60-70 degrees C.) but below the melt temperature (165-175 degrees C.), e.g., around 110-120 degrees C.

(148) A precursor tube is deformed in radial and axial directions by a blow molding process wherein deformation occurs progressively at a predetermined longitudinal speed along the longitudinal axis of the tube. As explained below, the deformation improves the mechanical properties of the tube before it is formed into the scaffold of FIG. 2. The tube deformation process is intended to orient polymer chains in radial and/or biaxial directions. The orientation or deformation causing re-alignment is performed according to a precise selection of processing parameters, e.g. pressure, heat (i.e., temperature), deformation rate, to affect material crystallinity and type of crystalline formation during the deformation process.

(149) In an alternative embodiment the tube may be made of poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide) (PLGA), polycaprolactone, (PCL), any semi-crystalline copolymers combining any of these monomers, or any blends of these polymers. Material choices for the scaffold should take into consideration the complex loading environment associated with many peripheral vessel locations, particularly those located close to limbs. Examples are described in U.S. patent application Ser. No. 13/525,145.

(150) The femoral artery provides a dynamic environment for vascular implants as various forces may crush, twist, extend, or shorten the device simultaneously. The force application may vary between point load to distributed load or a combination thereof and also as a function of time. Recent results have shown that bioresorbable scaffolds made from highly crystalline PLLA can provide crush recovery without causing a permanent and constant outward radial force on the vessel. The permanent and constant outward radial force may be the cause of late clinical issues with nitinol self-expandable stents. However, a remaining challenge with bioresorbable scaffolds is to make them optimally fracture resistant as a function of time; that is, to improve their fatigue life or survivability under a variety of dynamic loading environments. There is a continuing need to improve fracture toughness for a scaffold; and in particular a peripherally implanted scaffold.

(151) The fracture resistance of a vascular scaffold depends not only on the design and the material, but is also the manufacturing process and deployment parameters. Therefore it is in particular necessary to have a process, design, and a delivery system that allows the scaffold to be uniformly expanded and deployed. As a consequence of non-uniform deployment the various struts and crowns of a scaffold will potentially be exposed to very different forces and motions, which has a deleterious effect on the fatigue life.

(152) Alternative ways to improve the fatigue properties are through introduction of axial flexibility and the use of pre-designed fracture points, in particular in the connector links. The fracture points could function as precursors of actual fractures, e.g., crazes and cracks or small dimension of fracture distributed in the implant. A distribution or pattern of cracks or crazes may dictate or inform one of an expected toughness of the scaffold when subjected to a particular loading, e.g., torsion, radial force, tensile etc. Although it is understand that, due to the generally highly non-linear relationship between crack formation and a coupled loading environment, that is, simultaneously applied and time varying bending, torsion and axial loading, such predictive methods may not be applicable to all situations.

(153) Alternative ways to improve the fatigue properties are through introduction of axial flexibility and the use of pre-designed fracture points, in particular, fracture points in or near connector links as discussed in greater detail below.

(154) For a tube of FIG. 1 having a diameter about 7 mm and a wall thickness above 200 micro-meters and more specifically a diameter of 8 mm and a wall thickness of 280 micro-meters, the temperature at expansion is 235+/5 degrees Fahrenheit, the expansion pressure is 110+/10 psi and the expansion speed is 0.68+/0.20 mm/sec. The degree of radial expansion that the polymer tube undergoes can partially characterize the degree of induced circumferential molecular and crystal orientation as well as strength in a circumferential direction. In some embodiments the RE is about 400% and the AE is 40-50%. Other embodiments of processing parameters, RE and AE expansions considered within the scope of the disclosure are found U.S. application Ser. No. 13/840,257 filed Mar. 15, 2013.

(155) The strengthened and toughened cylindrical, polymer tube of FIG. 1 is formed into a scaffold structure, in one embodiment a structure having a plurality of struts 230 and links 234 forming a pattern 200 as shown in FIG. 2 (pattern 200 is illustrated in a planar or flattened view), which is about the pattern for the scaffold before crimping and after the scaffold is plastically, or irreversibly deformed from its crimped state to its deployed state within a vessel by balloon expansion. The pattern 200 of FIG. 2, therefore, represents a tubular scaffold structure (as partially shown in three dimensional space in FIG. 3), so that an axis A-A is parallel to the central or longitudinal axis of the scaffold. FIG. 3 shows the scaffold in a state prior to crimping or after deployment. As can be seen from FIG. 3, the scaffold comprises a framework of struts and links that define a generally tubular body. The cylindrical, deformed tube of FIG. 1 may be formed into this open framework of struts and links described in FIGS. 2-3 by a laser cutting device, preferably, a pico-second green light laser that uses Helium gas as a coolant during cutting.

(156) Referring to FIG. 2, the pattern 200 includes longitudinally-spaced rings 212 formed by struts 230. There are eight crowns or crests formed by the struts. A ring 212 is connected to an adjacent ring by no more than two links 234, each of which extends parallel to axis A-A. In this first embodiment of a scaffold pattern (pattern 200) two links 234 connect the interior ring 212, which refers to a ring having a ring to its left and right in FIG. 2, to each of the two adjacent rings. Thus, ring 212b is connected by two links 234 to ring 212c and two links 234 to ring 212a. An end ring (not shown) is an end ring connected to only one other ring.

(157) A ring 212 is formed by struts 230 connected at crowns 207, 209 and 210. A link 234 is joined with struts 230 at a crown 209 (W-crown) and at a crown 210 (Y-crown). A crown 207 (free-crown) does not have a link 234 connected to it. Preferably the struts 230 that extend from a crown 207, 209 and 210 at a constant angle from the crown center, i.e., the rings 212 are approximately zig-zag in shape, as opposed to sinusoidal for pattern 200. As such, in this embodiment a ring 212 height, which is the longitudinal distance between adjacent crowns 207 and 209/210 may be derived from the lengths of the two struts 230 connecting at the crown and a crown angle . In some embodiments the angle at different crowns will vary, depending on whether a link 234 is connected to a free or unconnected crown, W-crown or Y-crown.

(158) The zig-zag variation of the rings 212 occurs primarily about the circumference of the scaffold (i.e., along direction B-B in FIG. 2). The struts 212 centroidal axes lie primarily at about the same radial distance from the scaffold's longitudinal axis. Ideally, substantially all relative movement among struts forming rings also occurs axially, but not radially, during crimping and deployment. Although, as explained in greater detail, below, polymer scaffolds often times do not deform in this manner due to misalignments and/or uneven radial loads being applied.

(159) The rings 212 are capable of being collapsed to a smaller diameter during crimping and expanded to a larger diameter during deployment in a vessel. According to one aspect of the disclosure, the pre-crimp diameter (e.g., the diameter of the axially and radially expanded tube from which the scaffold is cut) is always greater than, or equal to a maximum expanded scaffold diameter that the delivery balloon can, or is capable of producing when inflated.

(160) A second embodiment of a scaffold structure has the pattern 300 illustrated in FIG. 4. Like the pattern 200, the pattern 300 includes longitudinally-spaced rings 312 formed by struts 330. There are twelve crests or crowns formed by the struts for each ring 312. A ring 312 is connected to an adjacent ring by no more than two links 334, each of which extends parallel to axis A-A. The description of the structure associated with rings 212, struts 230, links 234, and crowns 207, 209, 210 in connection with FIG. 2, above, also applies to the respective rings 312, struts 330, links 334 and crowns 307, 309 and 310 of the second embodiment, except that in the second embodiment there are 12, as opposed to 8 crests or crowns for each ring 312 for pattern 300.

(161) FIGS. 5A and 5B depict aspects of the repeating pattern of closed cell elements associated with each of the patterns 300 and 200, respectively. FIG. 5A shows the portion of pattern 300 bounded by the phantom box VA and FIG. 5B shows the portion of pattern 200 bounded by the phantom box VB. Therein are shown cell 304 and cell 204, respectively. In FIGS. 5A, 5B the vertical axis reference is indicated by the axis B-B and the longitudinal axis A-A. There are two such cells 204 formed by each pair of rings 212 in pattern 200, e.g., two cells 204 are formed by rings 212b and 212c and the links 234 connecting this ring pair, another two cells 204 are formed by rings 212a and 212b and the links connecting this ring pair, etc. Similarly, there are two cells 304 formed by rings 312b and 312c and the links 334 connecting this ring pair, another two cells 304 are formed by rings 312a and 312b and the links connecting this ring pair, etc.

(162) Referring to FIG. 5A, the space 336 of cell 304 is bounded by the longitudinally spaced rings 312b and 312c portions shown, and the circumferentially spaced and parallel links 334a and 334c connecting rings 312b and 312c. Links 334b and 334d extend parallel to each other and connect the cell 304 to the right and left adjacent ring in FIG. 4, respectively. Link 334b connects to cell 304 at a W-crown 309. Link 334d connects to cell 304 at a Y-crown 310. A W-crown refers to a crown where the angle extending between a strut 330 and the link 336 at the crown 310 is an acute angle (less than 90 degrees). A Y-crown refers to a crown where the angle extending between a strut 330 and the link 334 at the crown 309 is an obtuse angle (greater than 90 degrees). The same definitions for Y-crown and W-crown also apply to the cell 204. There are eight unconnected or U-crowns 307 for cell 304, which may be understood as eight crowns devoid of a link 334 connected at the crown. There are always two U-crowns between a Y-crown or W-crown for the cell 304.

(163) Additional aspects of the cell 304 of FIG. 5A include angles for the respective crowns 307, 309 and 310. Those angles are identified in FIG. 6A. For the scaffold having the pattern 300 the struts 330 have strut widths 363 and strut lengths 364, and the links 334 have link widths 363. Each of the rings 312 has a ring height 365. The radii at the crowns are, in general, not equal to each other. The radii of the crowns are identified in FIG. 6A. Cell 304 of pattern 300 may be regarded as a symmetric cell, by virtue of it always having two U-crowns on each side of a W-crown and Y-crown as shown.

(164) Referring to FIG. 5B, the space 236 of cell 204 is bounded by the portions of longitudinally spaced rings 212b and 212c as shown, and the circumferentially spaced and parallel links 234a and 234c connecting these rings. Links 234b and 234d connect the cell 204 to the right and left adjacent rings in FIG. 2, respectively. Link 234b connects to cell 236 at a W-crown 209. Link 234d connects to cell 236 at a Y-crown 210. There are four crowns 207 for cell 204, which may be understood as four crowns devoid of a link 234 connected at the crown. Cell 204 may also be regarded as a symmetric cell, by virtue of it always having one U-crown on each side of a W-crown and Y-crown as shown.

(165) Additional aspects of the cell 204 of FIG. 5B include angles for the respective crowns 207, 209 and 210. Those angles are indentified in FIG. 5B as angles 267, 269 and 268, respectively associated with crowns 207, 209 and 210. For the scaffold having the pattern 200 the struts 230 have strut widths 263a and strut lengths 264, the crowns 207, 209, 210 have crown widths 270, and the links 234 have link widths 263b. Each of the rings 212 has a ring height 265. The radii of the crowns are identified in FIG. 5A as inner radii 272 and outer radii 273.

(166) The V76 and V80 both have a symmetric cell design. A symmetric cell design (as shown in FIGS. 5A and 5B) has an equal number of U-crowns on each side of a W-crown or Y-crown. An example of an asymmetric cell design would be the V23 scaffold pattern, as described in US2011/0190871.

(167) A significant difference between the V80 and V76 is that the V76 (as well as other designs, described below) has eight crowns and two links whereas the V80 design has twelve crowns and two links. Having more crowns and therefore shorter bar arms than other designs, the V80 has a higher density of struts. For example, a 60 mm V80 scaffold has 33 rings and a total of 396 ring struts/scaffold, which can be compared to a total of 216 ring struts (27 rings8 struts per ring)/scaffold for the V76 design, and 200 ring struts/scaffold for the V59. In-vivo tests show that with a higher density of struts there is a lower late lumen loss for the V80.

(168) Crimping of the scaffold, as detailed in U.S. application Ser. No. 13/194,162, includes heating the polymer material to a temperature less then, but near to the glass transition temperature of the polymer. In one embodiment the temperature of the scaffold during crimping is raised to about 5 to 10 degrees below the glass transition temperature for PLLA. When crimped to the final, crimped diameter, the crimping jaws are held at the final crimp diameter for final dwell period. This method for crimping a polymer scaffold having crush recovery is advantageous to reduce recoil when the crimp jaws are released. After the final dwell period, the scaffold is removed from the crimper and a constraining sheath is immediately placed over the scaffold to minimize recoil. Examples of such a sheath are described in U.S. application Ser. No. 13/118,311 (62571.534).

(169) Testing of Scaffold Designs

(170) TABLE 2 provides a summary of the characteristics of various scaffolds that were tested in in-vitro and in-vivo to evaluate and compare various performance characteristics, as described in FIGS. 7-23 and the description that follows.

(171) TABLE-US-00009 TABLE 3 scaffold types Pattern Links Wall Tube Number connecting Scaffold thickness OD of adjacent Type (in) (mm) crowns rings material S-1, S-2 see U.S. application Ser. No. 13/252,121 (docket no. 104584.22) V2 .008 7 9 3 PLLA V23-008 .008 7 9 3 PLLA V23-014 .014 9 9 3 PLLA V59 .011 8 8 4 PLLA V62 .011 7 9 3 PLLA V76 .011 7 8 2 PLLA V78 .011 7 8 2 PLLA V79 .011 7 8 2 PLLA V79 - .011 8 8 2 PLLA-PCL PLCL90/10 (90/10) V80 .011 7 12 2 PLLA

(172) FIGS. 7-16 show results from various in-vitro tests, which were used to compare the mechanical properties of the V76 and V62 scaffolds to the V59 scaffold (see US2011/0190871 for full description of the V59). These tests were directed towards determining the radial strength and/or stiffness, acute recoil, crush recovery, pinching stiffness, and fatigue or fracture of the scaffold after repeated loading of the scaffold.

(173) The scaffolds were crimped to about a 0.085 in outer diameter (within the crimper head), sterilized by E-beam radiation, then expanded to 6.4 mm outer diameter using a 6.0 mm balloon prior to initiating the tests. The scaffold were made from PLLA and cut from a biaxial expanded tube using the process described earlier. Tests were conducted to assess the fracture toughness or number of discontinuous, cracked or broken struts appearing in the V59, V62 and V76 scaffolds under different test conditions.

(174) FIG. 7 compares results from a three-point bending test between the V59, V62 and V76 scaffolds. FIG. 8 compares results from a bending fatigue test between the V59, V62 and V76 scaffolds. For the three-point bending test and the bending fatigue test the bending axis is considered to be random, i.e., the statistical results depict the fatigue data for a bending axis about any axis passing through and perpendicular to the bending axis of the scaffold.

(175) FIG. 9 compares the axial force for a 10% static compression and extension of the V76 scaffold compared to the V59 and V62 scaffolds.

(176) FIG. 10 is a table showing the mean and standard deviation fractures at crowns and links for the V76 scaffold for one month and six month simulations of axial loading of the V76 scaffold when implanted within the femoral artery. For these tests the V76 scaffold was subjected to a 7% axial compression and extension at 37 degrees Celsius within a loaded silicon tubing simulating axial loading of the femoral artery.

(177) FIG. 11 compares the radial strength of the V76 and V62 scaffolds to the V59 scaffold.

(178) FIG. 12 compares the radial stiffness of the V76 and V62 scaffolds to the V59 scaffold.

(179) FIG. 13 compares the acute recoil of the V76 scaffold to the V59, V2 (as described in US2011/0190871) and V62 scaffolds.

(180) FIG. 14 compares the crush-recovery of the V76 scaffold to the V59 scaffold and V62 scaffolds.

(181) FIG. 15 compares the deploy-to-fracture of the V76 scaffold to the V59 scaffold and V62 scaffolds. This plot shows that the V76 begins to develop critical fractures at a higher diameter than the V59. FIG. 16 compares the pinching stiffness of the V76 scaffold to the V59 scaffold and V62 scaffolds.

(182) FIG. 17 shows the total percentage of discontinuity (cracked or broken struts and links) for the V59, V62, V76, V78, V79 and V80 scaffolds after 500,000 cycles of 7% axial compression of the scaffold (equivalent to 6-month walking).

(183) In-Vivo Testing

(184) FIGS. 18-21 compares minimum lumen diameter (MLD) or late loss and percentage of stenosis following a 28 day implant for each of the scaffold in TABLE 1. Each scaffold was implanted into the iliofemoral artery of a healthy porcine model and after 28 days explants were obtained in order to evaluate and compare the effectiveness of the polymer scaffolds in maintaining vascular patency. The implanted scaffolds were subject to various degrees of hip extension and flexion by the swine, which is believed to impose about 90 degrees bending, and about 3-15% axial compression of the implanted scaffold during a maximum hip and knee flexion.

(185) The scaffold were crimped to about a 0.085 in outer diameter (within the crimper head), sterilized by E-beam radiation, introduced into the animal model using standard procedures, then expanded within the artery to a 6.4 mm outer diameter using a 6.0 mm balloon. The scaffold were made from PLLA (exc. V79 PLLA-PCL) and cut from a biaxial expanded tube using the process described earlier.

(186) The data in FIGS. 18-21 were obtained using Quantitative Vascular Analysis (QVA) to determine the MLD and stenosis %. The number n in the figures represents the number of explants that were used to arrive at the mean and standard deviation values provide in FIGS. 18-21.

(187) FIG. 18 counts the total number of strut discontinuities found in the explants for the V59, V62, V76, V79 and V80 scaffolds.

(188) FIG. 19 compares the late lumen loss or minimum lumen diameter (MLD) in the explants for the V59, V62, V76, V79 and V80 scaffolds.

(189) FIG. 20 shows late lumen loss from FIG. 19 with statistical significance indicated between scaffolds. There is a significant p value of 0.011 (t-test) for the V80 scaffold data compared to the V59 scaffold data. Tables 2A and 2B, below, provides a summary of characteristics of the scaffolds. ACL and CRF indicate different locations for the in-vivo tests.

(190) TABLE-US-00010 TABLE 4A performance characteristics for scaffold types in TABLE 2 Stenosis Late Lumen loss Axial Fatigue % In vivo % (28 days) (28 days) (6 months) Stiffness fracture Scaffold (%) (mm) struts Links (N/mm) (28 days) Type FIG. 21 FIG. 19 FIG. 17 FIG. 17 FIG. 16 FIG. 18 V2 18 (ACL) 1.6 (ACL) 0.6 19 V23-008 10 (ACL) 1.8 (ACL) 0.6 18 V23-014 6 (ACL) 1.0 (ACL) 1.0 V59 24 (CRF)/ 1.5 (CRF)/ 8.1 31.7 1.24 38 (ACL)/ 10 (ACL) 2.1 (ACL) 28 (CRF) V62 2.3 15.7 1.62 V76 13 (CRF) 1.0 (CRF) 0.58 4.23 1.63 11 V78 16 1.6 0.60 0.00 1.36 16 V79 12 1.4 1.8 0.9 1.41 13 V79 (PLLA-PCL) 37 1.3 1.21 1 V80 12 0.4 0.00 0.00 0.91 8

(191) TABLE-US-00011 TABLE 4B performance characteristics for scaffold types in TABLE 2 Acute recoil (%) Recoil Crush Crush Crush Crush Scaffold FIGS. 13 after Recovery Recovery Recovery Recovery Type and 22 7 days (%) (18% crush) (33% crush) (50% crush) (67% crush) V2 2.5 V23-008 4.4 3.6 V23-014 V59 3.2 3.8 99% 94% 86% 82.5% V62 3.8 7.67 99% 96% 91% 82.5% V76 3.3 6.11 99% 96% 91% .sup.75% V78 3.0 5.91 V79 3.4 6.33 98% 94% 83.4%.sup. 75.3% V79 (PLLA-PCL) 3.0 98% 94% 88% .sup.76% V80 3.6 7.52 98% 94% 87% .sup.83%

(192) Referring to FIG. 17, the high number of crests provides the V80 scaffolds with unique flexibility and as a result is more fracture resistant than the other scaffolds when axial fatigue properties are evaluated by six-month simulated walking. The low fracture rate is also well translated and shows good correlation with in-vivo testing, as demonstrated in FIG. 18.

(193) Because the V80 scaffold has more struts/scaffold-length than the other scaffolds, the struts need to be less wide and as a result the radial strength of the V80 scaffold is significantly lower than other two-link scaffolds (V76-V79).

(194) Radial strength and stiffness are sometimes thought of as synonymous to scaffolding properties. According to this view, the V80 design would therefore appear to have a poor ability to maintain patency as compared to the other scaffolds. However, as seen in FIG. 19 the V80 scaffold shows a significantly lower late loss than the other more radially stiff scaffolds, even where the fracture percentages and/or rates are similar, e.g., V79 compared with V80. As shown in FIG. 20 the lower late loss shows statistical significance at 28 days relative to the other scaffold designs.

(195) While not wishing to be tied to any particular theory, the explanation for why the V80 design shows significantly lower late loss is believed to lie in the higher number of, or density of struts. With a greater number of struts the V80 provides more scaffolding (higher surface area and more support). In particular, when a strut is fracturing there is still significant support to push back the vessel. This aspect of the V80 may be understood in the following manner. For an equal number of fractures, there is a lower percentage of non-functioning strut-crown structures to the total number of strut-crown structures. Thus, while there may be an equal number of fractures as in other designs, the V80 is capable of providing a better or more consistent scaffolding over the vessel luminal surface because it has a larger number of intact crown-strut structures for every failed crown-strut structure.

(196) FIG. 21 shows that the V23-014 scaffold, which has a lower number of crowns but a higher wall thickness, produced a lower percentage of stenosis than the V80. This may be explained by an increase in the fatigue life of the scaffold struts (i.e., fewer fractures) since the thicker wall lowers the average stress for a strut for the same loading conditions.

(197) FIG. 22 shows acute recoil for the V78, V79, V80 and V79 scaffolds.

(198) FIG. 23 shows the radial strength (N/mm) and radial stiffness (N/mm per mm) for the V59, V62, V76, V78, V79 and V80 scaffolds.

(199) While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.