1.
Introduction
The capitol of Hubei province in China, Wuhan, became the center of an outbreak of
pneumonia of unknown cause in December 2019 [1]. This outbreak of pneumonia was the
emergence of the novel coronavirus (SARS-CoV-2 later named coronavirus disease 2019
or COVID-19) and continues summing cases in every continent in only a few months [1].
The World Health Organization (WHO) situation report 58 [2], indicated that, as of
the 18th of March, there had been 191,127 confirmed cases and 7,807 deaths around
the world. Due to its significant impact, the emergence of this novel coronavirus
has been declared a pandemic [1]. The executive governmental branch of the U.S. has
recently invoked the Defense Production Act to increase the domestic production of
medical supplies necessary for fighting the current pandemic [3]. The purpose of this
invocation will likely be use to drive private businesses to increase U.S. production
of Personal Protective Equipment (PPE) and other critical medical supplies and devices.
The Food and Drug Administration (FDA) reported that the COVID-19 outbreak would likely
impact the medical product supply chain, including potential disruptions to supply
or shortages of critical medical products in the U.S [4].
Additive manufacturing (i.e., 3D Printing) is uniquely well positioned to support
the shortage of critical medical devices [4]. Advancements in additive manufacturing
techniques and development of antimicrobial polymers, offer the possibility of printing
and customizing a wide range of medical devices. The critical limitation for the use
of polymeric materials to additively manufacture critical medical devices is the material
contamination by bacteria and viruses [5]. Previous investigations have shown strong
evidence of the use of different forms of copper as a biocidal agent [5–12] and the
use of copper nanocomposites to enhance the antimicrobial properties of polymers used
in the development of medical devices [9,11,12].
Several international efforts, such as the Open Source COVID19 Medical Supplies Group
(International) and Hack the Pandemic (Copper3D Inc) have made significant progress
using additive manufacturing to develop critical medical devices. The purpose of the
current manuscript is to provide a perspective of the role of additive manufacturing
in the COVID-19 pandemic with an emphasis in the mechanism of action and applications
of antimicrobial polymers for the development of critical medical devices.
2.
Theoretical mechanisms of the enhanced antimicrobial behavior of additive manufacturing
polymers
The development of an affective antimicrobial polymer for additive manufacturing seems
increasingly critical due to the extensive used of polymers in the prototyping of
critical medical devices. It has been suggested [12] that the addition of nanoparticles
of copper to polymers and the resulting antimicrobial properties have promising applications
to the development of medical devices associated to bacterial growth [12]. Previous
investigations have used copper nanocomposites to enhance the antimicrobial properties
of polymers used in injection molding and additive manufacturing to develop medical
device [9,11] Currently, the most commonly used polymer in additive manufacturing
is polylactic acid. Polylactic acid has been described as the main commodity polymer
derived from annually renewable resources, such as corn [13]. Thus, the use of a renewable
resource to produce antimicrobial polymers for additive manufacturing could significantly
assist the current medical product supply chain disruptions involving the manufacturing
of critical medical devices in austere clinical settings.
A recent publication in The New England Journal of Medicine by van Doremalen et al.
[8], suggested that copper was more effective than Stainless Steel in reducing the
COVID-19 virus viability, predicted decay, and Half-Life reduction. Specifically,
using a Bayesian regression model, the authors reported that after exposure to a copper
surface the median Half-Life reduction for the COVID-19 virus occurred at 0.774 hours
(C.I. = 0.427–1.19) and no viable COVID-19 virus was measured after 4 hours. Stainless
Steel, however, resulted in less desirable results showing a median Half-life reduction
at 5.63 hours (C.I. = 4.59–6.86) with viable virus detected up to 72 hours. Similarly,
the polymer, polypropylene, showed a low median Half-life reduction at 6.81 (C.I. = 5.62–8.17)
hours with viable virus also detected up to 72 hours [8]. Thus, standard polymers
have the potential problem of promoting COVID-19 virus viability for up to 3 days,
while copper surfaces reduce viral viability to only 4 hours.
The development of an affective antimicrobial polymer for additive manufacturing seems
increasingly critical due to the extensive used of polymers in the prototyping of
critical medical devices. It has been suggested [12] that the addition of nanoparticles
of copper to polymers and the resulting antimicrobial properties have promising applications
to the development of medical devices associated to bacterial growth [12]. Furthermore,
previous investigations have use copper nanocomposites to enhance the antimicrobial
properties of polymers used in injection molding and additive manufacturing to develop
medical devices [9,11].
The strong biocidal effects of copper found by van Doremalen et al. [8], are supported
by previous investigations [6,7] that have examined the viral deactivation properties
of copper oxide particles infused in textiles. Borkow et al. [7], found that the addition
of copper oxide into respiratory protective face masks resulted in potent anti-influenza
properties against human influenza A (H1N1) and avian influenza (H9N2) without altering
their physical barrier properties. Furthermore, Borkow [6] examined the capacity of
copper oxide-containing filters to neutralize viruses in suspension and found that
these filters resulted in a significant reduction of the infectious viral titers,
ranging from 1.1 log10 to 4.6 log10 for Yellow Fiber, Influenza A virus, Measles,
Respiratory Cynsytial, Parainfluence 3, HIV-1, Adenovirus type 1 and Cytomegalovirus
[6].
The porous configuration of 3D printed plastic parts (6–8 μm) [14] and the difficulties
to sterilize them [15] can complicate the use of additive manufacturing for the development
of critical medical devices, especially those exposed to large microbial loads [15].
However, the use of commercially available antimicrobial materials [11] and the implementation
of printing specifications settings resulting in fused extruded layers, can stop molecules
down to 0.000282 μm, significantly smaller than viruses, such as the virus associated
to COVID-19 (0.03 ± 0.01 μm) [16]. The recent elaboration of thermoplastics blends
with antimicrobial copper nanocomposites is a direct and practical approach to produce
antimicrobial thermoplastics [11]. The antimicrobial properties of copper, has been
enhanced by two main factors [9,12]. The first, is reducing the size of the copper
particles to the nanoscale (10 nm) [10] increasing the volume of copper that can be
added to a given solution or matrix as well as increasing the total surface area of
the particles releasing a higher amount of metal ions [9,12]. The second is incorporation
of copper nanoparticles into polymer matrices [9,12]. Copper nanoparticles on a polymer
structure present a stronger antimicrobial effect than microparticles or metal surfaces
by facilitating the adsorption of microorganisms on the polymer surface triggering
the diffusion of water through the polymer matrix [12]. In turn, water with dissolved
oxygen reaches the surface of embedded copper nanoparticles allowing the corrosion
processes to take affect by releasing copper ions. Copper ions reach the composite
surface damaging the microorganism cell membrane allowing the metal ions to enter
the cell and damage DNA, RNA, and other biomolecules [12,17]. The copper ions and
associated hydroxyl radicals produces DNA denaturalization damaging helical structures
[17]. This DNA and RNA damage has been shown to deactivate viruses [17]. Copper oxide
affected free viruses, virions being formed within the cytoplasm of cells during the
cell exposure to copper, and virions prior to their budding from the cells (Figure
1) [12,17]. Furthermore, a previous investigation [11] showed that a commercially
available antimicrobial additive manufacturing polymer (PLACTIVETM 1% copper nanoparticles
composite, Copper3D, Santiago, Chile) was up to 99.99% effective against Methicillin-resistant
Staphylococcus aureus and Escherichia coli. Thus, the unprecedented need of biocidal
polymers during a pandemic and the high accessibility of additive manufacturing equipment
and materials can drive the implementation of this technology to revolutionize the
manufacturing of critical medical devices when the supply chain is insufficient [9].
10.1080/17434440.2020.1756771-F0001
Figure 1.
Theoretical mechanisms for the enhanced antimicrobial behavior of additive manufacturing
polymers. (a) Copper nanoparticles on a polymer structure present a stronger antimicrobial
effect than microparticles or metal surfaces. Antimicrobial polymers facilitate the
process of attaching the microorganism on the polymer surface triggering the diffusion
of water through the polymer matrix. Water with dissolved oxygen reaches the surface
of embedded metal nanoparticles allowing dissolution or corrosion processes releasing
metal ions; metal ions reach the composite surface damaging the bacteria membrane.
Afterward, metal ions can diffuse into the interior of the microorganism. (b) The
antimicrobial mechanisms of nanoparticles of copper consist in producing cell membrane
damage via copper ions that damage polyunsaturated fatty acid compromising the structure
of the cell membrane and producing leakage of mobile cellular solutes resulting in
cell death. The redox cycling between Cu2+ and Cu1+ can catalyze the production of
highly reactive hydroxyl radicals, which can subsequently damage cell membrane lipids,
proteins, DNA, RNA, and other biomolecules. Once copper and associated hydroxyl radicals
are inside of the cell, it produces DNA denaturalization damaging helical structures.
Copper also damage and alter proteins acting as a protein inactivator via RNA, useful
to deactivate a wide range of viruses.
3.
Manufacturing of critical medical devices during a pandemic
COVID-19 patients are expected to experience pneumonia-like symptoms such as difficulty
in breathing. The appropriate supply of devices aimed to provide supportive care and
PPE will be critical in the next few weeks as the virus spread to a greater percentage
of the population [4]. The use of additive manufacturing and antimicrobial polymers
can be used in the prototyping of critical medical devices to accelerate the production
of the final device (i.e., connectors for ventilators) or as a final product (i.e.,
face masks).
As this pandemic develops, providing oxygen to patients experiencing severe symptoms
will be critical. It is expected that mechanical ventilators will play an important
role in the treatment of COVID-19 [8]. Hospitals in the U.S. are currently expecting
an unprecedented number of new COVID-19 cases. The shortage of mechanical ventilators
and health workers needed to operate them, may lead to a catastrophic scenario. A
previous investigation [18] showed that a single ventilator could be quickly modified
to ventilate four simulated adults for a limited time. The study showed significant
potential for the expanded use of a single ventilator during cases of disaster surge
involving multiple casualties with respiratory failure. The study used a customized
connector made of other readily available connective pieces to ventilate four lung
simulators for 12 hours [18]. The main limitations of using a customized connector
assembled with several connective pieces is the inability of reducing the size of
the connector to minimize dead space volume [18]. Furthermore, repurposing connectors
from other medical devices, can result in air leakage and infectious complications
from sharing one ventilator. The use of antimicrobial polymers can facilitate the
prototyping and clinical testing of these connectors with the objective of accelerating
the production of the final product using conventional manufacturing methods, such
as injection molding. The final production of these connectors could effectively expand
the use of a single machine to ventilate four simulated adults experiencing respiratory
failure due to COVID-19. The customization of the design can assist to minimize dead
space volume and prevent air leakage due to unnecessary connections. During critical
situations when doctors need to take life-or-death decisions due to the lack of ventilator,
the use of additive manufacturing would provide a feasible alternative for sharing
the use of a single ventilator. Table 1 includes a list of open-source critical medical
devices prototypes, including the ‘H Connector’ for standard ventilator and the antimicrobial
NanoHack 2.0 face mask among others.
10.1080/17434440.2020.1756771-T0001
Table 1.
Examples of open source critical medical devices.
Description
Source
\Limitations
NanoHack Protective Mask: Provides basic protection for from airborne particles.
Files: https://copper3d.com/hackthepandemic/
https://3dprint.nih.gov/discover/3dpx-013667
-Proof-of-concept design-Requires a proprietary antimicrobial material-Last resort
device, intended for the general public use-Difficult to sterilize
H Connector for Ventilators: Expanded use of a single ventilator to ventilate four
simulated adults
Files: https://copper3d.com/hconnector/
-Proof of concept design-Need mechanical characterization data-Only compatible with
22 mm tubbing-Difficult to sterilize
Prusa Protective Face Shield: Provides protection from large splashes.
Files: https://www.prusaprinters.org/prints/25857-prusa-protective-face-shield-rc1
-Requires third-party shield-Difficult to sterilize-Requires the use of antimicrobial
polymer
Reanimation valve: Connects to a Venturi Oxygen mask to regulate the percentage of
oxygen delivery.
Files: https://grabcad.com/library/respirator-free-reanimation-venturi-s-valve-1
-Proof of concept design-Need mechanical characterization data-Difficult to sterilize
Hands-Free Door Opener: Attaches to door handle to prevent microbial contamination.
Files: https://www.materialize.com/en/hands-free-door-opener
-Requires third-party hardware-Difficult to sterilize
Surgical masks are the most commonly used PPE by the general population, as well as
health care workers. Surgical masks are effective in blocking large-particle droplets,
but do not filter or block small particles in the air. The main reason, surgical masks
do not provide complete protection is due to the loose fit between the surface of
the mask and face allowing the entrance from small particle and large droplets. The
Centers for Disease Control and Prevention (CDC) recommends to safely discard used
masks in a plastic bag and put it in the trash [19]. The last and crucial step to
safely discard these masks is hand washing [19]. Previous published research [7] has
suggested that the high viral load remaining in surgical masks can be a source of
viral transmission both to the health care worker wearing the mask and to patients
[7]. This may happen when healthcare workers touch their mask and then fail to wash
their hands properly or when they dispose of the mask without proper safe disposal
precautions [7]. Thus, the used of additive manufacturing using antimicrobial polymers
to develop reusable face masks (Table 1) can significantly reduce the viral load remaining
on the mask protecting the end-users from contamination during prolonged mask wearing
[7].
4.
Conclusion
In conclusion, additive manufacturing is uniquely well positioned to support the shortage
of critical medical devices [4]. Advancements in the development of commercially available
antimicrobial polymers for additive manufacturing, offer the possibility of rapid
prototyping a wide range of critical medical devices. The strong scientific evidence
provided by previous investigations about the biocidal effects of copper nanocomposites
and the enhanced antimicrobial behavior of these composites in polymers, provides
an alternative for the rapid prototyping of critical medical devices during a pandemic.
Furthermore, the proposed theoretical cellular mechanism presented in the current
perspective, provides a potential pathway to the potential inactivation of the COVID-19
virus on surfaces of critical medical devices manufactured with antimicrobial polymers.
5.
Expert opinion
The current limitations of using additive manufacturing to produce critical medical
devices is the slow production time, verification of the quality of the print, and
compliance with regulatory entities. The slow production time of additive manufacturing
can be offset by the flexibility of using and transport a raw material to austere
environments for final production. The industrial production of antimicrobial polymers
and additive manufacturing of on-demand critical medical devices are described in
Figure 2. The ability to produce antimicrobial polymers using a renewable source that
can be stored and transported as a raw material could significantly assist the current
medical product supply chain disruptions involving the manufacturing of critical medical
devices in austere clinical settings. It can be argued that current state of additive
manufacturing may not be mature enough to develop a final product ready to be implemented
in a clinical setting. However, the true benefits of accessible additive manufacturing
techniques, such as fused deposition modeling, during a fast-developing pandemic are
the ability to produce functional complex geometries both quickly and at low cost.
These functional complex geometries and the rapid prototyping of experimental medical
devices accelerates the developing process of a final product of a medical device
and its implementation. The use of more sophisticated additive manufacturing methods
and materials, such as Selective Laser Sintering and Polyamide 12 powdered thermoplastic
polymers embedded with copper nanoparticles composite would significantly improve
the durability facilitating the implementation of antimicrobial medical devices in
clinical settings.
10.1080/17434440.2020.1756771-F0002
Figure 2.
The manufacturing process of antimicrobial critical medical devices using an antimicrobial
polymer. The process starts with corn fermentation (corn to Lactic Acid), condensation
(Lactide) and polymerization (Polylactic acid; PLA). The addition of copper nanocomposite
additive to pellets at different concentrations allows the development of a multipurpose
antimicrobial filament. The recyclable characteristics of this filament facilitate
the production of new antimicrobial medical devices in austere environments.
The use of additive manufacturing of critical medical devices has facilitated efforts
of international groups, such as the Open Source COVID19 Medical Supplies Group (International)
and Hack the Pandemic (Copper3D Inc) to respond to disruptions to the medical product
supply chain by providing alternative options to access critical medical devices.
As additive manufacturing technology matures and continues to permeate varied industries
and products, it is apparent that some level of regulation must be developed to ensure
consistent quality and reproducibility across fabrication types, manufacturers and
materials. A recent FDA Draft Guidance titled ‘Technical Considerations for Additive
Manufactured Devices’ [20] serves as a first step toward defining government policy
regarding the use of additive manufacturing for critical medical devices. These regulatory
efforts validate the use of additive manufacturing to rapid prototype critical medical
devices and accelerate the process of final production and implementation. It is feasible
that within a 5-year period, additive manufacturing and the use of antimicrobial polymers
will play a crucial role in the development of on-demand and implementation of antimicrobial
critical medical devices in clinical settings.