Drug-eluting balloon (DEB) and drug delivery catheter (DDC) based treatments are increasingly being offered and used for the treatment of coronary, peripheral, neurovascular, and ENT applications. European markets have already seen a larger acceptance of these therapy choices ahead of the US markets. However, large randomized studies are underway in various stages of data collection to clearly quantify the advantages of balloon catheters over drug eluting stents, longstanding procedures like percutaneous transluminal angioplasty, surgical interventions (e.g., atherectomy or grafts), and drug therapy-like tissue plasminogen activator.
Various clinical trials have produced data that indicate the balloon design (specifically its ability to deliver drugs at both the correct location and improve drug uptake) and the procedural techniques used to be among the major factors that determine the success or failure of a therapy. Design concepts include hole/opening size and density, complex geometry of the balloon and catheter with multiple lumens, and surface structure modifications while maintaining a vigil on cost control.
Advances in laser micromachining technology — which include the capability of compensation for material and geometry variations and feature placement — offer device engineers an expanded toolbox to create better DEB/DDC devices, as well as keeping costs under control.
Laser Micromachining: A Brief Primer
In its broadest sense, laser micromachining applies to a specific window of all laser manufacturing where the feature sizes range between 1 μm and 1 mm. The features can be measured as size, depth, or density. Running a large gamut of wavelengths, lasers offer material removal methods based on a thermal process (400–10,600 nm visible & IR lasers like Nd: YAG or CO2) or a photochemical ablation process (<400-nm UV lasers like excimer or higher harmonics of solid state lasers). In addition, the latest buzz in the industry is from ultrafast lasers — material removal is determined less by the wavelength and more by the extremely high energy densities (temporal and spatial) delivered in a pico- or femtosecond timeframe. A typical laser micromachining system has four components: laser source, optical system for laser beam delivery, mechanical system for device handling and manipulation, and camera vision and software controllers to integrate all the components.
For thin-film metals and polymer devices, UV laser technology enables devices to be manufactured according to a highly desired combination of smallest feature sizes and highest quality. This is possible due to non-thermal material removal and the inherent high resolution of short wavelength light.
To offer a comprehensive and successful laser manufacturing solution, the provider must answer three fundamental questions:
1. What type of laser and starting parameters should be used (based on material)? 2. What is the optical design (based on feature spec and cost)? 3. What mechanical system should be used (based on feature location and device geometry)?
Catheter Micromachining — Laser Manufacturing Advantage
Catheters are the primary mode of delivering devices, drugs, and surgical tools through ports to the human body. Coronary, peripheral, neurological, renal, and gastrointestinal diseases requiring intervention use catheters therapeutically.
The peripheral arterial disease (PAD) market is a rapidly growing market for development and treatment. With a gradual reduction in profits from the established interventional cardiology arena, device manufacturers are encouraging a larger investment in PAD. Drugs, stents, atherectomy, graft, balloons, and a combination of these therapies can be used to treat peripheral diseases. To that end, catheters are used as a delivery vehicle and current designs improve on drug delivery and arterial wall uptake, mechanical plaque breakdown, and subsequent removal.
The neurovascular market is seeing significant growth from therapies that target aneurysms, tumors, ischemic stroke, and neural vascular malformations. Micro-catheters are used in conjunction with stent-type retrieval systems to treat and remove emboli. Coils are inserted in skived ports in catheter lumens to deliver targeted therapy for preventing rupture of aneurysms and/or neurostimulation.
Laser micromachining of catheters offers the ability to include design elements for improvement of, for example: drug delivery, smaller catheter size for reduction in post-treatment recovery, position and design of ports, and selective removal of coatings on braided catheters to improve flexibility.
The following is an example of drilling holes and skives at specified locations on a polymer multi-lumen DDC. Common materials chosen for catheters include Pebax®, nylons, and fluoropolymers (e.g., FEP and polyimide). Various design and material challenges are presented and solved with new advancements in laser micromachining. (See Figure 1)
Design Criteria: Uniform precise holes less than 100 μm in diameter and skives with no bulk material damage
Manufacturing Solution: UV Lasers
UV laser wavelength offers a highresolution and photochemical ablation process that produces holes and skives with no manufacturing artifacts and with tight tolerances. Solid-state lasers are available at 355 and 266 nm wavelengths; excimer lasers operate at 308, 248, and 193 nm. A rule of thumb is that the shorter the wavelength, the higher the resolution and quality of ablated features.
Design Criteria: Compensate for variable wall thickness
Manufacturing Solution: Excimer Laser Pulse Control
• With the capability of removing material at 100–300 nm per pulse, excimer lasers can offset a significant percentage of catheter extrusions with variable wall thickness. An initial measurement of incoming lot of extrusion is taken to determine the degree of nonconcentricity. • Based on the process, the laser beam can be programmed to achieve a constant pulse dose based on the thickest wall dimension or compensate pulses per location using end point detection techniques.
Design Criteria: Close-packed 10–30 μm holes in lumen for more uniform delivery of thrombolytic agents; surface modification
Manufacturing Solution: Mask Projection UV Excimer Machining
• Mask projection refers to the use of a large, higher-order beam to illuminate a mask with a desired hole pattern and then producing a demagnified image on the workpiece. UV excimer lasers are the most common lasers used in these methods. The advantage over a small beam direct-write approach is essentially an economy of scale and potentially a faster and better uniformity of the drilled holes.
• A single array of holes can have different diameters and shapes to optimize drug delivery.
• Excimer lasers remove material at typical rates of 100–300 nm/pulse. This allows for excellent depth control and uniform sidewall profile.
Design Criteria: Partial removal of coating to increase flexibility
Manufacturing Solution: Homogenized Excimer Beam
Optical design is used to deliver a modified beam with a uniform energy density in a shape that matches the desired feature shape. Beams as long as 3" can dramatically improve the throughput and provide uniform circumferential stripping of coatings; atherectomy devices requiring selective removal of coatings are potential beneficiaries of this method. (See Figure 2)
Design Criteria: Multi-lumen catheter design to deliver multiple devices and drug formulations at the site of treatment
Manufacturing Solutions: Vision Alignment, Mandrel Usage, Automated Handling
Mandrel Use: Catheter designs involving lumen sizes smaller than the beam depth of focus require use of mandrels to prevent damage to the back wall or septum. Mandrels also help with identifying lumens for machining. Downside is the increased handling time for mandrel insertion and subsequent removal.
Mechanical Part Handling: Catheters range in length from a few millimeters for neurological applications, to more than a meter for peripheral vascular therapies. Handling systems also play an important role in presenting the catheter at the site of machining; for peripheral therapy DDC, motion stage design involves choosing a combination of long travel stages, vertical compensation for range of catheter diameters, and direct drive rotary stages for precise lumen positioning. Automation systems provide for pick and place, highly accurate indexing, and the ability of batch processing.
Vision System: The combination of multi-lumen construction and reduc - ed stiffness over extended lengths result in lumen twist along the length of the catheter. This results in a manufacturing problem when holes or skives need to be placed along the entire length of the catheter. Part handling assists with accurate positioning, using a vision system to identify the correct lumen by looking at both lumen attributes and the mandrel when available, and ensures that operator intervention is reduced.
Drug-Eluting Balloons — Laser Manufacturing Advantage
For drug-eluting balloons, laser micromachining offers several advantages that have been discussed in the previous section. Balloons offer a more challenging issue — their use in various therapies is on the rise and their design is becoming more complicated (when taking advantage of newer materials and balloon manufacturing techniques). From reservoirs for drugs, to delivering electrical stimulation via embedded electrodes, balloons cover a wide range of applications. In addition, balloon geometry is inherently three-dimensional and manufacturing methods have to be able to cover the entire universe of designs.
Used as a drug reservoir with targeted site delivery, micropore balloons are characterized by a very high density of holes (typically 50 μm or smaller in diameter) placed within one to two diameters of each other. The design criterion requires delivery of the therapeutic agent in a highly controlled and uniform fashion to improve uptake and also to minimize vascular wall damage due to the pressurized flow. (See Figure 3)
Weeping Balloons and Drug-Eluting
Balloons These balloons have proprietary coating technologies for the various therapeutic drugs. The balloon surface can be modified to create channels for drug or fluid flow, or provide a pathway for electrodes to be in contact with the aneurysm (or lesion). The intent for surface modification is to improve the efficacy of the coating and/or improve surface contact.
Design Criteria: High-density hole pattern on cylindrical an gio plasty balloon body
Manufacturing Solutions: UV Excimer Laser 193 nm with Mask Projection
UV excimer lasers at 193 nm wavelength with a mask projection technique can rapidly drill the large volume of dense holes with tight tolerances. Typically for hole sizes between 10 and 50 μm, tolerances range from 1 to 10 μm. The actual tolerances are determined by laser-material interactions (material coupling well with the laser light) and balloon positioning control. Hole sizes down to 1 μm are possible in thin-walled balloons with active Z-axis (vertical) compensation.
Design Criteria: Surface modification or holes drilled on neck and body of balloon
Manufacturing Solution: Mask motion, Part motion, Part mapping
Balloon Mapping: Laser micromachining requires the part surface to stay at a constant distance from the laser beam and the ablation area to be normal to the beam. This requirement ensures that all drilled holes are of the correct size and taper characteristics, and all drilled holes are of the same shape.
Using vision systems, the balloon surface geometry is mapped to determine the shape and any large changes in circumferential or longitudinal distance from the laser beam. This mapping allows the engineer to program the motion controllers to compensate for shape changes.
Mask design/motion: Use a hole pattern based on balloon geometry and then program the motion of the mask to match the part rotation (also referred to as COM — Coordinated Opposing Motion)
Laser control: Program the laser pulse firing rate and the energy density if necessary to ensure that all locations receive the same amount of energy and pulse dosage.
Design Criteria: Non-planar, conical, or other complex shape for balloon geometry
Manufacturing Solution: 9-axes micromachining technology
The laser micromachining requirement is to have all surfaces normal to the laser beam when being ablated. To achieve this, a combination of balloon mapping, mask motion, and part motion control is used. Part Motion: X, Y, Z, theta, tilt, and yaw. Mask motion: rotational and linear — 3 axes.
The net effect of the above is a rapid drilling protocol that achieves remarkable uniformity of drilled holes on both planar and non-planar surfaces with all holes meeting the tolerances and shape requirement. (See Figure 4)
Various balloon and catheter methodologies are being developed to address disease states. For a medical device design engineer, it is important to use clinical and point-of-use data to improve current device designs for effectiveness while simultaneously making the new device cost-beneficial to the patient and the health care system. Laser micromachining has helped enable this by utilizing advancements in hardware, optical, vision, and mechanical systems to become a very attractive option as a manufacturing method.
As medical device sizes shrink and their geometries become exotic, the laser micromachining toolkit continues to evolve and remove obstacles in the path of their manufacturability.
This article was written by Diwakar Ramanathan, Technical Sales Engineer for Resonetics LLC, Nashua, NH. For more information, Click Here