Advanced Manufacturing Technologies in Healthcare Today

[Beam Hardening, courtesy of Radiopaedia]

Advanced Manufacturing is the use of innovative technology to improve products or processes. Today, these advancements are especially prominent in the healthcare industry, where we see innovations in prosthetics, dentistry, and medical models. 

I recently had the opportunity to speak at RAPID + TCT in Detroit to provide a snapshot of what can be achieved in the medical industry with the technology available today including 3D scanning, DICOM, 3D printing, and post-printing support removal and finishing techniques. Let’s take a look at some. 

3D Scanning 

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3D Scanning technology (and Structured Light Scanning in particular) is well-suited to applications within the realm of cosmetic and other prosthetics requiring 3D capture of external anatomical data. 3D scanning lets you quickly collect a mesh file of the part of the body and then, using surface-to-solid body conversion methods found in 3D CAD software like SOLIDWORKS, turn that patient data into solid CAD models. 

These solid models can be used directly or manipulated to create lattice structures, generatively designed structures, and other useful textures. Users can then reconvert the file into a mesh (e.g., STL) file for 3D printing. 

DICOM Segmentation and Processing

Digital Imaging and Communications in Medicine (DICOM) files are patient-specific anatomical data taken from MRI, CT, ultrasound, and other medical imaging technologies used to capture internal patient anatomy. 

For DICOM to be used for 3D printing, we must first overcome a few restrictions common in modern-day medical scanning.

Factors that affect scanning quality include:

  • Beam hardening — the contrasting of streaks with bone imaging (a problem with metal implants)

  • Blooming — calcium deposits and heterotopic bone appearing larger than they are

  • Radiation exposure (the longer the scan is, the better the imaging) works best on cadavers (per the ALARA (As Low As Reasonably Achievable) principle)

  • Timing of the scan (imagine trying to scan a heart while it’s beating) also known as bolus tracking utilizes a radio-opaque media which is clearer contrast in the imaging

  • Layer thickness

[Blooming, courtesy of DARConline ]

[Blooming, courtesy of DARConline]

Once usable scanning data has been obtained, it is necessary to choose the appropriate DICOM segmentation software and follow the standard DICOM processing procedures shown in the tables below. 

[Courtesy of 3D Printing in Orthopaedic Surgery ]

[Courtesy of 3D Printing in Orthopaedic Surgery]

[Courtesy of Stratasys]

[Courtesy of Stratasys]

After selecting and segmenting the intended patient anatomy, materials and colors must be chosen to create a structure. Applications for this kind of DICOM to 3D print data are pre-surgical testing, patient communication, and medical training and education. 

3D Printing

3D printing offers a multitude of different materials and methods to create physical parts. Below are some of the basics surrounding FDM (Fused Deposition Modeling) thermoplastics and PolyJet photopolymers.

FDM Thermoplastics

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Certain FDM materials such as ULTEM are sterilizable, opening up applications for drill guides, cutting guides, and tool fixtures. 

PolyJet Photopolymers


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Top of the line PolyJet 3D printers are capable of multi-material, multi-durometer, and multi-color part assemblies with customization down to the voxel. With these capabilities, obtaining segmented anatomical data and specific colors, opacities, and shore values to different anatomical structures and tissue types is possible. 

Post-Processing 

image 9.png

Both in dental and medical models, support removal is extremely important. PolyJet models, specifically that are created with high complexity and thin anatomical structures, have a high risk of damage and breakage during the support removal process. 

Geometries similar to the larynx model above have incredibly small features that can easily break during traditional support removal processes. It is ideal to perform bulk removal whenever relevant, as well as using appropriate soluble support removal tanks to gently agitate the rest of the support structures away, releasing the final model. Companies like PostProcess Technologies have created focused technologies to address these challenges. 

Surface Quality 

Surface smoothness can be measured as roughness average (Ra), or in other words, the average of surface heights measured across a surface. Raw, as-printed, typically require additional post-processing to improve the surface finish. For medical devices, metal finishing or surface smoothing quality depends on the model material of the part, lubrication chemicals, and the tumbling media. PostProcess Technologies equipment makes it easy to smooth any FDM, PolyJet, or 3D printed medical grade metals like titanium.

Gradient surface finish plays an important role to highlight, for example, bone tissue which requires a textured surface to adhere to. On the flip side, making medical models too smooth could ruin applications. For example, over-smoothing a dental mold could affect dimensional accuracy and inhibit the release of the vacuum-formed retainer. 

All of the technology listed above plays a vital role in additive manufacturing in healthcare today and will continue to advance and evolve for years to come. Being in the middle of an industrial revolution means we can continue to expect exciting medical breakthroughs for doctors, patients, and technologists. 

Sex Comparison of Knee Extensor Size, Strength and Fatigue Adaptation to Sprint Interval Training

Background:
Regular sprint interval training (SIT) improves whole-body aerobic capacity and muscle oxidative potential, but very little is known about knee extensor anabolic or fatigue resistance adaptations, or whether effects are similar for males and females. The purpose of this study was to compare sex-related differences in knee extensor size, torque-velocity relationship and fatigability adaptations to 12 weeks SIT.
Methods:
Sixteen males and fifteen females (mean (SEM) age: 41 (±2.5) yrs) completed measurements of total body composition assessed by DXA, quadriceps muscle cross-sectional area (CSAQ) assessed by MRI, the knee extensor torque-velocity relationship (covering 0 – 240°·sec-1) and fatigue resistance, which was measured as the decline in torque from the first to the last of 60 repeated concentric knee extensions performed at 180°·sec-1. SIT consisted of 4 x 20 second sprints on a cycle ergometer set at an initial power output of 175% of power at VO2max, three times per week for 12 weeks.
Results:
CSAQ increased by 5% (p=0.023) and fatigue resistance improved 4.8% (p=0.048), with no sex differences in these adaptations (sex comparisons: p=0.140 and p=0.282, respectively). Knee extensor isometric and concentric torque was unaffected by SIT in both males and females (p>0.05 for all velocities).
Conclusions:
12 weeks SIT, totalling 4 minutes very intense cycling per week, significantly increased fatigue resistance and CSAQ similarly in males and females, but did not significantly increase torque in males or females. These results suggest that SIT is a time-effective training modality for males and females to increase leg muscle size and fatigue resistance.
Corresponding author: Dr Liam Bagley, School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Manchester, UK, M1 5GD Email: liam.bagley@mmu.ac.uk Tel: (+44) 161 247 1145
Copyright © 2019 by the National Strength & Conditioning Association.

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Time flies when you're at RPE13: How exercise intensity influences perception of time

Previous studies have shown that there are some changes in our perception of time during exercise, but the relationship between intensity level and these perceptions is unclear. Therefore, the purpose of this study was to determine the effect of exercise intensity on prospective time estimations. Twenty-two trained runners (10 male, 12 female; age 25±6 years) participated in three 30-minute treadmill runs that were perceptually regulated at rating of perceived exertion (RPE) levels of 13 (“somewhat hard”), 15 (“hard”) and 17 (“very hard”). Prospective time assessments, in which subjects estimated durations of 1, 3, 7 and 20 seconds, were obtained immediately before exercise, during (at 10 min. and 20 min.) and after exercise. A 3 (RPE) x 4 (timepoint) x 4 (estimated duration) repeated measures ANOVA was completed. There was a significant main effect of RPE level (p=.013). Post hoc tests revealed that time estimations at RPE17 were significantly lower than those at RPE13 (p=.021). The main effects of timepoint and estimated duration were not significant (both p≥.05), and no interactions were present. However, there was a trend for time estimations to decrease in all conditions as exercise progressed, with a rebound after cessation of exercise. This study showed a clear effect of exercise intensity on time perception. Specifically, the subjects perceived time to pass by more slowly as intensity increased.
Corresponding Author: Nicholas J Hanson, Ph.D. 1903 W. Michigan Ave Department of Human Performance & Health Education Western Michigan University Kalamazoo, MI 49008 email: njhanson@gmail.com phone: 269.387.2670
This study was funded by an internal university research grant. None of the authors have any conflicts of interest to declare.
Copyright © 2019 by the National Strength & Conditioning Association.

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Kumovis’ Clean Room 3D Printer

Setting parameters on the R1 3D printer [Image: Kumovis]

A new medical-focused 3D printer integrates clean room technology.

Medical 3D printing is a fast-growing area. Interest is high, as personalized medical devices like implants can be made ‘at the push of a button.’

Of course it’s not quite that easy, but precise 3D printing is enabling more patient-specific care with on-site technicians capable of creating devices just for an individual. Rather than an off-the-shelf, three-sizes-fit-most model like many medical providers have become used to, 3D printing is enabling a this-size-fits-you model.

Any medical application, though, brings with it more hoops to jump through. As it should: when something is going to be used in contact with or inside the human body, every assurance is needed to ensure the safety of that human.

Kumovis R1


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kumovis_r1_compact_3d_printer_design.JPG

Munich-based Kumovis has now introduced its first production 3D printer with (optional) clean room integration, the R1.

Already on-site with three pilot customers, the R1 is also commercially available as of this month. The system, which looks to be a delta-style extrusion 3D printer, is offered through direct sale or as a subscription model; all availability information (presumably including pricing) is by request.

Key features include homogeneous build chamber heating up to 250°C, with an integrated temperature management system, enabling the use of high-temp materials including the desirable PEEK, as well as generally improved layer adhesion through that temperature control. “Comprehensive monitoring and documentation options” also ensure high process reliability during each print.

The integrated clean room environment is made possible through the temperature control and filtration systems: “In this way, defects caused by foreign particles in the component can be avoided.”

“With the Kumovis R1, we are excited to provide medical technologists with a resource-efficient additive manufacturing system that meets their high requirements, and what is more, leads FLM processing of high-performance plastics to industrial maturity,” said Co-Founder and Managing Partner Stefan Leonhardt. “In addition, with partners such as the software experts from Hyperganic, we will be able to provide rapid access to individualized medical products, and consequently help creating added value for patients and doctors alike.”

Software Partnership

The R1 operates with integrated software from Hyperganic.

Hyperganic’s Managing Director, Lin Kayser, noted that the company “works closely with printer manufacturers” to bring in its software. The partnership with Kumovis brings in Hyperganic Print software-based print control to enhance automation and offer users more print parameter control.

On its About page, the software company notes that:

“Hyperganic builds software to design objects that are as complex, functional, elegant and sustainable as Nature.”

That’s especially helpful — considering the subjects at hand for Kumovis are indeed naturally-designed. Mimicking the functionality and complexity of the human body, even for seemingly simple models and implants, requires exquisite attention to detail, making advanced software a necessity.

Advanced Medical 3D Printing

A 3D printed cranial implant [Image: Kumovis]

A 3D printed cranial implant [Image: Kumovis]

Kumovis certainly has its believers already.

In October 2018, the company issued a brief statement:

“We are happy to [announce] that we closed our seed financing round together with High-Tech Gründerfonds and a family office. We will use the 7-digit funding for final product development and the go to market in July 2019.”

Seven digits puts the investment at at least €1 million. While they just barely missed their July goal for market readiness — the R1 was officially available as of 1 August — their strategic approach seems to be essentially on track.

There are a few things this young startup is doing very right: substantial seed funding, strong partnerships, high-temperature capabilities with tight control, application-specific focus, getting equipment into the hands of early adopters.

The Kumova R1 may just prove intriguing for medical users.

Via Kumovis

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It’s Nice To Be First In 3D Printing; It’s Better To Be Best

[Stock image / via Gartner]

A tweet from Fabbaloo friend Julie Reece has me thinking about market positioning in 3D printing.

Until very recently, Julie was the VP of Marketing at Rize, leading the messaging efforts for the company’s unique 3D printer and helping to position them in the market. She has years of experience in the 3D printing industry, including with Mcor, 3D Systems, and Z Corp, and has now established her own consulting business, J. A. Reece Marketing Solutions. She knows, in short, what she’s talking about.

Sometimes it can seem like marketing might be the underdog department in a startup. But if no one knows what you’re talking about — they can’t talk about it.

We often come back to the importance of messaging when it comes to market position. These conversations are only becoming more necessary as additive manufacturing continues to gain prominence across more applications, picking up new users who aren’t entrenched in the depths of these 30-plus-year old processes.

First To Market

With more than three decades of development, 3D printing isn’t wholly “new” anymore.

Only it still is.

Companies and job shops are adopting additive manufacturing more and more today. We’re talking about rising rates of adoption, and that means a lot of beginner-level users are taking up increasingly advanced equipment.

In the 1980s and 1990s, early adopters flocked to the stalwarts in rapid prototyping. For the most part, these meant 3D Systems for SLA and Stratasys for FDM, as these companies employed the originators of these original 3D printing processes. The trend continued, as the first-to-market companies had the edge as, for quite a while, the only ones on the market.

But they’re not alone anymore.

ASTM International currently recognizes seven unique categories of additive manufacturing processes, and more are being evaluated for consideration in expanding these categories. The means of 3D printing are expanding — and so are the providers.

The advantage of having been first to market is dwindling as other companies commercialize similar technologies. During my recent visit to SLM Solutions, which holds patents key to originating SLM technology, the team noted that they needed to strategically refocus now that being first wasn’t in and of itself enough anymore:

“There’s been a sense of ‘we were first and the others are playing catch-up’ — now they’re starting to catch up. So what do we do now?” asked SLM Solutions Application Engineer Kyle Adams.

Only On The Market

So if being first isn’t enough — what is?

Being the best. Being the only. As Julie astutely points out:

If there’s one thing I’m sick to death of working on the media side of this industry, it’s announcements of a “new world’s first” machine/process/software/anything. At this point, frankly, a lot of these are utterly inaccurate and simply aren’t the first in the world. The world is a big place and 3D printing is a very global industry.

But even if it is a genuine “world’s first” — so what?

These are the kinds of sparkly marketing-speak that don’t necessarily mean anything. It all sounds the same after a while.

What doesn’t sound the same? A unique solution.

Not by calling it a “unique solution” but by actually being one. That’s the key to real, valuable messaging. Can a press release convey actual, realizable, verifiable results that solve real-world problems? If so, that’s the ticket.

What the market is calling for is a solution to a problem. If your system is the only one that can provide a solution, you have just gained interest.

For the most part in 3D printing, those solutions come down to what manufacturing needs:

  • Speedier solutions — faster time to market

  • Lower-cost solutions — reduction in manual labor, materials costs, time spent both making and post-processing parts

  • Lighter-weight solutions — automotive and aerospace applications in particular are always looking to provide strength with lower weight / less mass

  • Part consolidation — making in one part what had previously been dozens or more components welded together strengthens the whole and removes assembly time

  • Advanced geometries — making the ‘previously unmakeable’

  • Verified solutions — repeatability, durability, qualification; ensure quality and real-world viability

  • Secure solutions — IP protection and other security measures are coming more into focus as digital manufacturing gains traction in Industry 4.0

  • Familiar / varied materials — especially for companies familiar with conventional/subtractive manufacturing, working with familiar materials eases the way into working with a new process, especially for qualified applications

Being the only provider of any of these or myriad other potential benefits will position a company strongly in the eyes of industry.

It doesn’t have to be all of them, of course; an educational customer is looking for price, safety, and reliability, while an aerospace contractor needs high strength and FAA approval.

Finding a marketing niche means being smart about what’s being offered — and being sure that that messaging is on point.

Never undervalue what good messaging can deliver: an open door to the market.

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Want To Write For Fabbaloo?

Writing for Fabbaloo? [Source: Pixabay]

Every day you’ll see stories in Fabbaloo from our regular contributors, but have you ever thought you might see your words in our pages, through a guest post on Fabbaloo?

It’s entirely possible; we do accept guest posts, with some caveats. Typically we’ll host perhaps one or two each week, but they’ve undergone some scrutiny from us prior to publication.

That scrutiny is required because we receive a startling number of requests to post material on our site. Some days we receive several such requests. Unfortunately, most of them come from unscrupulous SEO organizations wishing to push links to one product or another. Even worse, many of these publishing requests are for entirely unrelated products that would seem very out of place in our ecosystem.

These we routinely decline.

But we do want to have more views on 3D printing technology in our pages, and for that we require your help. We seek material and opinions from individuals who have been involved in 3D printing and have something important to say. We’re particularly interested in new approaches to using 3D printing that could benefit the community at large.

We have prepared a set of guidelines we use to vet incoming publishing proposals, which you can review to see if there’s a good fit. We discuss what we are specifically looking for, and more importantly what we are not looking for. If you are able to meet our guidelines, there is a pretty good chance we’ll publish your material.

If you’re doing something interesting and want to tell everyone about it, by all means let us know. Send us an email with a brief explanation of who you are, and the opinion, project or thoughts you’d like to promote in the 3D printing community.

We’ll take a look at your proposal and consider it carefully. If we’d like to proceed and publish your story, we’ll work with you to ensure it reads well and has some impact.

But you think you’re not a writer? That’s okay, too. As long as you have a good topic and a draft of your material, we can help you complete it.

We don’t care who you are, as long as you have a good idea that people would like to hear. Whether you’re a seasoned 3D print veteran working in the field for decades, a new person to the technology or anything in between, we’d like to hear from you!

Please review our guidelines and application process and consider a submission.

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The ICP0 protein of herpes simplex virus 1 (HSV-1) down-regulates major autophagy adaptor proteins, sequestosome 1 (SQSTM1/p62) and optineurin (OPTN), during the early stages of HSV-1 infection. [Virus-Cell Interactions]

Herpes Simplex Virus type 1 (HSV-1) infects mucosal epithelial cells and establishes life-long infections in sensory neurons. Following reactivation, the virus is transferred anterograde to the initial site of infection or to sites innervated by infected neurons, causing vesicular lesions. Upon immunosuppression frequent HSV-1 reactivation can cause severe diseases such as blindness and encephalitis. Autophagy is a process whereby cell components are recycled, but it also serves as a defense mechanism against pathogens. HSV-1 is known to combat autophagy through the functions of the 134.5 protein, which prevents formation of the autophagophore by binding to Beclin-1, a key factor involved in the elongation of the isolation membrane, and by redirecting the protein phosphatase 1 α (PP1α) to dephosphorylate the translation initiation factor 2α (eIF2α) to prevent host translational shutoff. Other viral proteins that counteract innate immunity negatively impact autophagy. Here, we present a novel strategy of HSV-1 to evade the host, through the down-regulation of the autophagy adaptor protein sequestosome (p62/SQSTM1) and of the mitophagy adaptor optineurin (OPTN). This down-modulation occurs during the early steps of the infection. We also found that the Infected Cell Protein 0 (ICP0) of the virus mediates the down-modulation of the two autophagy adaptors in a mechanism independent of its E3 ubiquitin ligase activity. Cells depleted of either p62 or OPTN could mount greater antiviral responses, whereas cells expressing exogenous p62 displayed decreased virus yields. We conclude that down-regulation of p62/SQSTM1 and OPTN is a viral strategy to counteract the host.

Importance

Autophagy is a homeostatic mechanism of cells to recycle components, as well as a defense mechanism to get rid of pathogens. Strategies that HSV-1 has developed to counteract autophagy have been described and involve inhibition of autophagosome formation or indirect mechanisms. Here, we present a novel mechanism that involves down-regulation of two major autophagy adaptor proteins, sequestosome 1 (p62/SQSTM1) and optineurin (OPTN). These findings generate the question: Why does the virus target two major autophagy adaptors if it has mechanisms to block autophagosome formation? P62/SQSTM1 and OPTN proteins have pleiotropic functions, including regulation of innate immunity, inflammation, protein sorting and chromatin remodeling. The decrease in virus yields in the presence of exogenous p62/SQSTM1 suggests that these adaptors have an antiviral function. Thus, HSV-1 could have developed multiple strategies to incapacitate autophagy to ensure replication. Alternatively, the virus could target another antiviral function of these proteins.

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Human Cytomegalovirus pUL37x1 is Important to Remodeling of Host Lipid Metabolism [Virus-Cell Interactions]

Human cytomegalovirus (HCMV) replication requires host metabolism. Infection alters the activity in multiple metabolic pathways, including increasing fatty acid elongation and lipid synthesis. The virus-host interactions regulating the metabolic changes associated with replication are essential to infection. While multiple host factors, including kinases and transcription factors, important to metabolic changes that occur following HCMV infection have been identified, little is known about the viral factors required to alter metabolism. In this study, we tested the hypothesis that pUL37x1 is important to the metabolic remodeling that is necessary for HCMV replication using a combination of metabolomics, lipidomics, and metabolic tracers to measure fatty acid elongation. We observed that fibroblast cells infected with wild-type (WT) HCMV had similar levels of metabolites as those infected with a mutant virus lacking the UL37x1 gene, subUL37x1. However, we found that relative to WT-infected cells subUL37x1-infected cells had reduced levels of two host proteins that were previously demonstrated to be important for lipid metabolism during HCMV infection—fatty acid elongase 7 (ELOVL7) and ER-stress related kinase PERK. Moreover, we observed that HCMV infection results in an increase in phospholipids with very long-chain fatty acid tails (PL-VLCFAs) that contain 26 or more carbons in one of their two tails. The levels of many PL-VLCFAs were lower in subUL37x1-infected cells compared to WT-infected cells. Overall, we conclude that although pUL37x1 is not necessary for network-wide metabolic changes associated with HCMV-infection, it is important to the remodeling of a subset of metabolic changes that occur during infection.

Importance

Human cytomegalovirus (HCMV) is a common pathogen that asymptomatically infects most people and establishes a lifelong infection. However, HCMV can cause end-organ disease that results in death in the immunosuppressed and is a leading cause of birth defects. HCMV infection depends on host metabolism, including lipid metabolism. However, the viral mechanisms for remodeling metabolism are poorly understood. In this study, we demonstrate that the viral UL37x1 protein (pUL37x1) is important for infection-associated increases in lipid metabolism, including fatty acid elongation to produce very long-chain fatty acids (VLCFAs). Further, we found that HCMV infection results in a significant increase in phospholipids, particularly those with VLCFA tails (PL-VLCFAs). We found that pUL37x1 was important for the high levels of fatty acid elongation and PL-VLCFAs accumulation that occurs in HCMV-infected cells. Our findings identify a viral protein that is important for changes to lipid metabolism that occurs following HCMV infection.

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Contributions of Lower Body Strength Parameters to Critical Power and Anaerobic Work Capacity

This study examined the contribution of lower body strength and isokinetic peak torque measures to the prediction of critical power (CP) and anaerobic work capacity (AWC). Fourteen recreationally trained males (mean ± SD age: 22.4 ± 2.5 yrs; height: 177.9 ± 7.7 cm; body mass: 84.2 ± 12.4 kg) with anaerobic training experience completed this study. The lower body strength measures included one repetition max (1RM) bilateral back squat [BSq], isokinetic peak torque at 30°·sec-1 [PT30] and isokinetic peak torque at 240°·sec-1 [PT240]) of the dominant leg. The CP and AWC were determined from the 3-min all-out CP cycle ergometer test (CP3MT), with the resistance set at 4.5% of the total body mass. The CP was defined as the mean power output over the final 30s of the test and the AWC was calculated using the equation, AWC = 150s (P150 – CP), where P150 equals the mean power output for the first 150s. Stepwise regression analyses indicated that only BSq contributed significantly to the prediction of AWC (AWC = 0.0527[BSq] + 8.094 [SEE = 2.151 kJ; p = 0.012]), with a correlation of r2 = 0.423. None of the strength parameters significantly predicted CP. These findings indicated that BSq strength accounted for 42% of the variance in AWC, but lower body strength was not related to CP. The current results indirectly supports the unique metabolic characteristics of both CP and AWC in providing separate measures of an individual’s aerobic and anaerobic capabilities, respectively.
Corresponding Author: M. Travis Byrd, Department of Kinesiology and Health Promotion, University of Kentucky, 100 Seaton Building, Lexington, KY 40506-0219, Phone: 859-200-6859, Fax: 859-323-1090, Email: mark.travis.byrd@uky.edu
Copyright © 2019 by the National Strength & Conditioning Association.

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Attenuation of equine lentivirus alters mitochondrial protein expression profile from inflammation to apoptosis [Cellular Response to Infection]

Equine infectious anemia virus (EIAV) is an equine lentivirus similar to HIV-1, targets to host immune cells and causes life-long infection in horses. The Chinese live EIAV vaccine is attenuated from long-term passaging of a high virulent strain in vitro. The parent pathogenic strain (EIAVDLV34) induces a host inflammatory storm to cause severe pathological injury of animals. However, the vaccine strain (EIAVDLV121) induces a high level of apoptosis to eliminate the infected cells. To investigate how these processes are regulated, we performed a comparative proteomics analysis and functional study in equine monocyte-derived macrophages (eMDMs), and found that divergent mitochondrial protein expression profiles caused by EIAV strains with different virulence lead to disparate mitochondrial function, morphology and metabolism. This in turn promoted distinct transformation of macrophage inflammatory polarization and intrinsic apoptosis. In EIAVDLV34 infected cells, a high level of glycolysis and increased mitochondrial fragmentation were induced, resulting in M1-polarized pro-inflammatory type transformation of macrophages and subsequently producing a strong inflammatory response. Following infection with EIAVDLV121, the infected cells were transformed into M2-polarized anti-inflammatory macrophages by inhibition of glycolysis. In this case, decrease of mitochondrial membrane potential and impairment of electronic respiratory chain led to increased levels of apoptosis and ROS. These results are correlated with the viral pathogenicity loss and may help to understand the key mechanism of lentiviral attenuation.

IMPORTANCE

Following viral infection, the working pattern and function of the cell can be transformed through the impact on mitochondria. It still unknown how mitochondrial response changes in the cells infected with viruses in the process of virulence attenuation. EIAVDLV121 is the only effective lentiviral vaccine for large-scale use in world. EIAVDLV34 is a parent pathogenic strain. Unlike EIAVDLV34-induced inflammation storms, EIAVDLV121 can induce high levels of apoptosis. For the first time, we found that, after altering mitochondrial protein expression profile, EIAVDLV34 infected cells are transformed into M1-polarized type macrophages to cause inflammatory injury and the intrinsic apoptosis pathway is activated in EIAVDLV121 infected cells. These studies shed light on how the mitochondrial protein expression profile change from cells infected by pathogenic or attenuated lentivirus strains to drive different cellular response, especially from inflammation to apoptosis.

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