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Featured Project / 3FX Brings Ophthalmology into Focus

We sat down with 3FX's Science Director Kartik Mohan to discuss the challenges of producing high-end medical animation content in the rapidly expanding therapeutic area of ophthalmology.

What are the challenges around creating animated medical education content for ophthalmology?

The eye, of course, is an extremely complex and precise structure, highly specialized to enable vision. It's populated by a gigantic cast of cellular and molecular actors, all functioning together on an epic scale.

The eye has been likened to a microcosm of the human body; many attributes of different organ systems are recapitulated within it, on a tiny scale. You have a cornea that's mostly extra-cellular matrix with a thin epithelial layer; the aqueous humor, an ultrafiltrate of blood, whose molecular contents are reflective of serum levels; the vitreous humor, which provides structural support, and has many similarities to cartilage and synovial fluid; the retina and optic nerves, which are a direct and specialized extension of the CNS; and of course the lens, which is an organized matrix of crystalline proteins with an entirely unique function. You have muscles, nerves, glands and vasculature whose functions are coordinated by several mechanisms, each of them vulnerable to a host of factors that may induce dysfunction.

Above: Shot from a recent project depicting the retinal micro environment with retinal ganglion cells and vasculature

Conceptually, an important challenge is to communicate a strong understanding of how these components work together in sustaining vision, and the great diversity of factors implicated in their dysfunction, which can lead to a number of eye diseases. The disease states we've dealt with range from events as relatively straightforward as local trauma and infection, to complex systemic problems of nervous and circulatory dysfunction or metabolic imbalance that may manifest themselves as ocular pathologies. To explain many diseases of the eye, we have to go beyond the eye and illustrate regulatory mechanisms whose dysfunction may arise far away.

One artistic challenge is that the anatomical structure of the eye, with its multiplicity of components, has been very well studied and characterized. We have to be extremely precise in creating anatomical, tissue and cellular-level CGI environments of the eye. Any first-year medical student could tell instantly if there was the slightest inaccuracy in our representation; so we must get every last detail absolutely right, every time.

Can you talk about some of the projects you've worked on in the area of ophthalmology?

Sure. As I said, eye diseases can arise from events at every level, from local infection to systemic dysfunction. We've covered the entire gamut in our animations of ocular pathophysiology.

At the simplest level there's trauma, and the need to contain post-surgical inflammation. Some years ago, we created a short animation for Alcon's DUREZOL (difluprednate ophthalmic emulsion) which focused mainly on the molecular design, and on enhanced drug delivery through an emulsion formulation.

Below: DUREZOL ANIMATION

Then there's bacterial infection of the ocular surface. Our brief promotional video for Inspire's AZASITE (azithromycin ophthalmic solution) was patient-focused, directed at healthcare professionals, and emphasized indications and dosing schedules rather than going into details of the macrolide antibiotic's mechanism of action. For both DUREZOL and AZASITE, the brief was to create a clean, compelling look that effectively communicated the medications' key clinical advantages. We stayed away from highly realistic cellular detail that could clutter up the visual message. For AZASITE in particular, we had fun creating some facial character animation as well.

Below: AZASITE ANIMATION

In contrast, the film we made for Bausch & Lomb's BESIVANCE (besifloxacin ophthalmic) delved deeply into the molecular mechanisms of quinolone antibiotics against the common pathogens involved with bacterial conjunctivitis. I enjoyed sinking my teeth into the research, tracking down Protein Data Bank molecular models of the quinolone target enzymes (bacterial gyrase and topoisomerase IV) and developing an animation script that accurately portrays the disruption of bacterial DNA replication and transcription by besifloxacin. Our technical director and medical illustrator, Gary Welch, used 3D software to create a dynamic simulation of the DNA replication process, accurately portraying strand synthesis, supercoiling and topoisomerase activity. We were so particular about scientific detail that we identified and illustrated specific mutations in the S. aureus GyrA gene (S84A, E88G) that commonly induce resistance.

Below: BESIVANCE ANIMATION

ZIRGAN (ganciclovir ophthalmic gel) was another Bausch & Lomb project I found particularly interesting, partially because a lot of my graduate work in molecular biology was centered on viruses. It's a very broad-scope animation that examines HSV-1 infection at many levels, through a series of breathtaking digital panoramas created by our senior medical animator Joel Dubin. We depict the primary outbreak, and the subsequent transport of viral nucleocapsids, through photo-realistically rendered gross anatomy of the face and trigeminal nerve. There are a series of tissue-level environments that show how virus particles infect the ophthalmic nerve and travel to the corneal surface, causing recurrent episodes of herpetic keratitis. Finally, there are richly detailed portrayals of the molecular actors, illustrating the competitive inhibition of DNA polymerase by the dGTP analogue Ganciclovir triphosphate, and the subsequent disruption of viral DNA synthesis. Here, again, we used Protein Data Bank molecular models for accuracy, and Gary designed dynamic simulations of DNA replication with eukaryotic cellular machinery, subtly different from the prokaryotic mechanisms seen in bacterial cells.

Below: ZIRGAN ANIMATION

The ZIRGAN video conveys a complex scientific message, covering disease state, mechanism of action and drug differentiation; all this in an intensely compelling and dramatic visual style, without compromising on scientific accuracy. It's one of the pieces we're most proud of, here at 3FX.

What about ocular manifestations of systemic disease states, like diabetes?

We produced a series of videos for Novo Nordisk that illustrates the various macro- and micro-vascular complications of diabetes, one of which dealt specifically with diabetic retinopathy.

The challenge here was to maintain a strong, consistent look-and-feel that ties together the overall concept of system-wide metabolic imbalance, even while depicting processes and environments specific to ocular pathology. Chronic hyperglycemia promotes the accumulation of glucose within insulin-independent cells throughout the body, abnormally triggering a number of metabolic pathways that cause oxidative stress; retinopathy is only one of the consequences. Insulin resistance further contributes to the dysfunction of mechanisms that regulate vasodilation. Our approach was to examine the effects of these cellular abnormalities on precipitating the clinically observable effects of progressive diabetic retinopathy.

Below: RETINOPATHY ANIMATION

We begin by illustrating the disruptive structural changes, aneurysms and intra-retinal hemorrhages that herald the non-proliferative phase of diabetic retinopathy. We go on to describe how ECM component accumulation thickens capillary basement membranes, and address the emergence of “cotton-wool spots” as a consequence of nerve-fiber layer ischemia. In the proliferative phase, we depict angiogenesis in the intra-retinal microvasculature, leading to optic disk or retinal surface detachment, and explain the contributions of macular edema and hard exudates to vision loss.

This video covers a lot of ground, illustrating the development and progression of diabetic retinopathy within a relatively short run-time; similarly, other videos in the series deal with neuropathy, nephropathy, peripheral arterial disease and macrovascular complications such as atherosclerosis. Viewed together, they provide clinicians with a succinct but detailed overview of a complex and multi-factorial disease.

3FX has some spectacular flat-screen 3D animations in ophthalmology. Have you ventured into alternative display technologies for this therapeutic area?

We certainly have.  On the largest scale we've created full-dome animations, a form to which the spherical interior of the eye lends itself very well. Combined with 3D stereoscopic rendering, full-dome ophthalmic animations make for an unmatched immersive experience.

We've also designed holographic displays where a 3D image of the eye appears to be suspended in mid-air, so that the viewer can walk around and take it in from different sides, or even interact with it. It's the same idea as those plastic models you might see in a doctor's office, but taken to a whole other level, because our holograms are fully animated. They can be sectioned to view processes in motion, or exploded to reveal components at any level of detail you like.

Below: OPHTHALMIC HOLOGRAHY ANIMATION

  
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