3D Medical Devices

Considerations for Sterilization and Biocompatibility of 3D-Printed Orthopedic Devices

Thor Rollins, Martell Winters, and Matthew Jorgensen, PhD collaborated on a whitepaper that is available for download: Considerations for Sterilization and Biocompatibility of 3D-Printed Orthopedic Devices

This whitepaper is an in-depth look at the various biocompatibility and sterilization considerations surrounding 3D-printed orthopedic devices. 3D-printed orthopedic medical devices are gaining attention and popularity due to their potential for enhanced biocompatibility, customizability, and cost-effectiveness. As of late 2015, FDA had cleared more than 85 total 3D-printed medical devices, with more regulatory clearances on the horizon.

The whitepaper is available for download on the Qmed website http://directory.qmed.com/download-this-whitepaper-to-learn-about-the-file068515.html or click HERE.

Quick Guide to FDA’s Draft Guidance on 3D Printed Devices

Posted in Printing Services by MDDI Staff on May 24, 2016

By: Matthew R. Jorgensen, PhD

A new leapfrog guidance from FDA gives a glimpse into the agency’s thinking on 3D printed medical devices.

On May 10, 2016, FDA released a leapfrog guidance document on the technical considerations for additive manufactured or 3D printed devices. Leapfrog guidance documents provide valuable information on what is in the regulatory pipeline and allow interested parties to have a voice in the development of FDA guidance.

Continue reading on the MDDI website for key points from the draft guidance pertaining to the testing of medical devices.

 

3D Printed Devices and Biocompatibility: Material Aeration

By: Matthew R. Jorgensen, PhD; Paul L. Littley, B.S.E.

The previous three posts addressed biocompatibility concerns of 3D printed devices considering additives to the raw materials, the material curing process, and post-printing finishing processes. Both thermoplastics and photopolymers contain additives (oligomers, plasticizers, preservatives, etc.) that are freshly redistributed through the printing process. Following printing, consideration must be given to the amount of time required for aeration of the device before use to allow additives near the surface to diffuse and volatize from the surface. Aeration of additives out of a device can be compared directly with aeration of ethylene oxide (EO) residuals, which is commonly used for in-package sterilization. Desorption of EO, and its residual byproducts, is a common concern for medical devices sterilized with this sterilization method. The amount of time required for aeration depends on the device materials, geometry, and concentrations of additives of concern. While calculation of precise aeration times for 3D printed plastic additives is outside of the scope of this blog post, the need for adequate aeration is well illustrated by examining the law of diffusion governing the desorption of volatiles from a solid, and by comparing the diffusion coefficients of plastic additives to that of EO gas.

Figure 1

Desorption of EO or a plastic additives is limited by the ability of the chemical to diffuse to the surface of the device (Figure 1) and so is well described Fick’s laws of diffusion. Fick’s first law states that the number of molecules diffusing through a particular surface per second is proportional to both the diffusion coefficient D (which depends on the aeration temperature, the molecule’s size, and surface geometry) and the concentration gradient dC/dx of the chemical across the surface. A larger diffusion coefficient and greater concentration difference lead to faster diffusion and desorption from a material.

Fick

Fick’s First Law

As explained in part 1 of this blog series, when a raw thermoplastic material goes through the 3D printing process any additives are redistributed evenly through the printed material. Likewise, unreacted photopolymer precursors and other components are distributed throughout 3D printed photopolymers. Even distribution results in a large concentration gradient of the additives at the material surface, where the concentration goes from the full formula concentration just inside the surface to zero outside. The large initial concentration gradient leads to an initial strong desorption, which tapers off slowly over time as the material develops an additive depleted surface. As an example we will consider EO and the plasticizer diethylhexyl phthalate (DEHP) in polypropylene (PP), for which diffusion data is readily available.

Suppose we wish to print PP which has a 0.1% by mass concentration of the plasticizer DEHP. A typical device might weigh 20 g, which leads to 200 mg total DEHP. The raw material is a resin fiber which is well aerated prior to use, resulting in a thin additive depleted layer on the surface and a very low rate of desorption. During the printing process, the resin is melted and drawn through a very fine nozzle – redistributing the DEHP evenly throughout the material. Immediately, DEHP along with other volatiles start to desorb off of the material into the surroundings. The process slows exponentially as a depleted layer forms over the surface until – eventually – the material again resembles the raw material (Figure 2). The amount of time required for this process is directly related to the diffusion coefficient of the compound in the material. DEHP has a diffusion coefficient in PP of 3.8×10-11 cm2/s at 40°C, while EO has a diffusion constant in PP of 5.9×10-8 cm2/s at 40°C; this means that DEHP diffuses approximately 1,500 more slowly than EO. This is why that new car smell we all love, which is a cocktail of plasticizers and other additives, lasts long after the car leaves the factory.

Figure 2

A typical EO sterilization process allows for 24-48 hours of heated aeration time, though many companies choose to follow this with additional days of ambient aeration. Based on a comparison of diffusion coefficients, the amount of time required for aeration of 3D printed medical devices could be significantly longer depending on the concentrations and types of additives. The diffusion coefficient and rate of desorption increase dramatically with temperature, so any post-printing sterilization steps at elevated temperatures may facilitate desorption. Decisions regarding the aeration time needed for 3D printed polymer devices should be based on observation, taking into account all post-printing steps and understanding that desorption will continue slowly over time.

As 3D printed medical devices continue to rise in popularity, so will the scrutiny on their biocompatibility. Assessment of these devices should consider not only the raw materials used, but the curing parameters, post-printing finishing processes, and aeration time.

 

3D Printed Devices and Biocompatibility: Post-Printing and Finishing

 

Matthew R. Jorgensen, PhD; Alexa Tatarian, BS

In the previous two posts, the biocompatibility of 3D printed devices was discussed with consideration for the possible compounds added to the raw materials for workability and the polymer precursors and byproducts associated with photopolymerized structures. In both of these cases, the discussion focused on the materials designed to be part of the final structure. Here, the introduction of compounds from the sacrificial support material, post-printing rinsing, and finishing processes are discussed; all of which are secondary to the device material itself.

3D printing offers facile creation of complicated devices by depositing the structure additively along with a selectively removable support material. The support material allows the printing of overhanging parts by providing a structural platform for the device material, and can act as a thin layer between parts that are printed very close to each other but should be prevented from fusing (think, for example, of printing a device with movable gears). Without sacrificial support materials, 3D printed designs would be severely limited. Because the support material is not intended to be part of the finished device, it may be overlooked as a possible source of biocompatibility issues.

After printing, the sacrificial support material (which is generally dissolvable in a water based cleaning solution) must be removed. The compatibility of the support material depends on the printing technology used. Methods that deposit thin lines of thermoplastic use a special water-soluble polymer or break-away material, while photopolymerization methods may use a loosely polymerized gel or unexposed photopolymer as support materials. Laser sintering methods (often used to produce metal and metal oxide parts) use un-sintered precursor powder.

Each support material and removal method raises potential concerns from a biocompatibility perspective.

3D 3

Following removal of support materials, 3D printed devices may undergo subsequent finishing processes. Extruded thermoplastics may be smoothed through exposure to heated solvent vapors such as acetone or methylene chloride. The combination of heat and natural affinity of the solvent for the material creates ideal conditions for adsorption into the material surface. Metal parts may undergo passivation processes that introduce surface contaminants. Desorption of volatiles from 3D printed material will be discussed next week.

3D Printed Devices and Biocompatibility: Details of the Material Curing Process

By: Matthew R. Jorgensen, PhD

The last blog post reviewed how 3D printed medical devices present unique challenges from a biocompatibility assessment perspective due to their highly customized material properties. Additives to raw materials used in 3D printing are required to enhance workability. For 3D printed materials which are exposed to UV light and are cured, the details of the exposure and curing process can influence the chemical composition and other properties of the final material. This article will provide an overview of the chemistry involved in the exposure and curing of photopolymers (also known as photoresists), which is required to understand how these factors have the potential to impact the biocompatibility of the final structure.

Photopolymers are composed of at least 4 critical components: monomers, oligomers, photo-initiator, and solvent (Figure 1). UV light is the activator, setting off a cascade of reactions that result in the polymerization of monomers and oligomers into a durable solid. Monomers and oligomers contain chemical groups that allow them to bond to themselves and each other into long chains.

3D

Monomers are the most basic single units of a polymer. Oligomers are larger and more complex than monomers, with chemical groups between the bonding ends that are tailored to customize and fine-tune the final material properties. Having monomers and oligomers with light-sensitive reactive groups would make them unstable and affect the polymer properties. Therefore, a photosensitive component is added which degrades in the presence of UV light to highly reactive radical products that activate the monomers and oligomers allowing them to join together.

Photopolymerization is a complex process, where the balance of different chemical components, the intensity of UV light exposure, the duration of UV light exposure, and temperature are the critical variables. Much research has gone into the composition and balance of the different chemical components, so within the context of 3D printing this variable is highly optimized. The other factors, however, may be user defined and subject to evolution over time. The intensity of the UV light may change over the lifetime of the light source. Since the unexposed photopolymer absorbs UV light, the intensity also varies slightly over the thickness of the photoresist. The exposure time may depend on the write speed of the 3D print job. The temperature, which is potentially variable, is critical because this factor determines the mobility of the photopolymer components; higher temperatures allow reactants to move through the volume of the photoresist and polymer chains to readjust their positions.

3D 2

Even under the most ideal printing conditions, each of the reaction steps in the polymerization process proceed at different rates and never to 100% completion. Therefore, the result of the photopolymerization reactions are, at best, a well-formed polymer with traces of precursors, intermediates, and byproducts as contaminants. As conditions drift from ideal, the proportion of contaminants increases.

The specific monomers, oligomers, photo-activators, and other additives used in the 3D printing of photopolymers are propriety and the types and proportions of potential contaminants are dependent on how ideal the printing conditions are. Therefore, under clinical conditions it is possible for a wide range of compounds to leach from a 3D printed photopolymer device, and the range of these is dependent on the curing parameters. In approaching the biocompatibility assessment of 3D printed photopolymer devices, these extractable/leachable compounds should be expected. Understanding the toxicological impact of these compounds requires expert review and evaluation on a case-by-case basis. Consideration should be given not only to the raw materials going into the printed photopolymer, but the details of the curing process which may be subject to process and environmental variability.

Check back next week to learn more post-printing material rinsing and finishing processes.

3D Printed Devices and Biocompatibility

By: Matthew R. Jorgensen, PhD; Audrey P. Turley, B.S., RM(NRCM), CBA(ASQ)

3-D Blog Post

The use of three-dimensional (3D) printing techniques to address challenging fabrication problems has become mainstream over the past decade. While this rich resource has extended fabrication of personalized medical devices to the limit of our imagination, the myriad materials and morphologies available present a unique concern from a toxicological perspective. A range of standalone 3D printers are commercially available with compatible materials ranging from plastics to oxides and metals. Raw materials used in the fabrication process often have highly customized properties, achieved through the use of proprietary additives and specific microscale morphologies which can affect the overall biocompatibility of the finished device. Therefore, 3D printed medical devices require versatile approaches to the assessment of their biocompatibility that consider several factors which will be addressed in turn over this four-part blog series:

  1. Possible additives to raw materials which enhance workability
  2. Details of the material curing process
  3. Post-printing finishing and rinsing processes
  4. Time allowed for aeration between device manufacture and use

Possible additives to raw materials which enhance workability

3D printed plastic materials can be grouped by the printing technology used; generally either photolithography or direct writing of thermoplastic materials. In both of these cases, one or more materials are printed in tandem with a sacrificial filler material that provides structural support during the printing process. Photolithographic methods use a mixture of polymer precursors called photoresist which polymerize into a durable solid on exposure to light. If the photoresist requires light with intensity above a certain threshold, extremely fine resolution on the order of hundreds of nanometers is possible by scanning tightly focused laser light through the photoresist. Direct writing involves the partial melting of raw materials through a heated nozzle into fine layers. The structure and support material are deposited layer by layer, gradually building from the ground up. A compromise between photolithography and direct writing is also possible. In a process similar to inkjet printing, which produces thousands of colors by mixing three or four primary colors, different combinations of photoresists can be mixed and printed followed by exposure and polymerization with UV light.

Each technology for 3-D printing of plastic involves materials with highly customized properties, enabled by their unique chemistries. Photolithography involves polymer precursors, photosensitizers, other additives, and solvents. Following exposure, precursors and reaction byproducts remain embedded in the structure raising concerns regarding their potential to leach out during clinical use. Thermoplastics used in direct writing processes include plasticizers and other additives essential for their workability but which may cause concern as some of these additives are not biocompatible. Following melting and drawing through the writing nozzle, the additives are redistributed through the material and the surface area is increased exponentially. These processes increase the availability of potential toxicants to their surrounding matrix in the body and potentially a clinical exposure risk if not understood.

Evaluation of the biocompatibility of 3D printed devices should consider chemicals which are novel additives to otherwise well-known materials, as well as byproducts of the polymerization process. The availability of these chemicals for extraction into the matrix surrounding the device must be evaluated along with an assessment of their potential toxicological impact on a case-by-case basis.

Tune in next week to learn more about the details of the material curing process and the role it plays in the biocompatibility of 3D printed medical devices.