Ergonomic handheld OCT angiography probe optimized for pediatric and supine imaging

: OCT angiography is a functional extension of OCT that allows for non-invasive imaging of retinal microvasculature. However, most current OCT angiography systems are tabletop systems that are typically used for imaging compliant, seated subjects. These systems cannot be readily applied for imaging important patient populations such as bedridden patients, patients undergoing surgery in the operating room, young children in the clinic, and infants in the intensive care nursery. In this manuscript, we describe the design and development of a non-contact, handheld probe optimized for OCT angiography that features a novel diverging light on the scanner optical design that provides improved optical performance over traditional OCT scanner designs. Unlike most handheld OCT probes, which are designed to be held by the side of the case or by a handle, the new probe was optimized for ergonomics of supine imaging where imagers prefer to hold the probe by the lens tube. The probe’s design also includes an adjustable brace that gives the operator a point of contact closer to the center of mass of the probe, reducing the moment of inertia around the operator’s fingers, facilitating stabilization, and reducing operator fatigue. The probe supports high-speed imaging using a 200 kHz swept source OCT engine, has a motorized stage that provides +10 to − 10 D refractive error correction and weighs 700g. We present initial handheld OCT angiography images from healthy adult volunteers, young children during exams under anesthesia, and non-sedated infants in the intensive care nursery. To the best of our knowledge, this represents the first reported use of handheld OCT angiography in non-sedated infants, and the first handheld OCT angiography images which show the clear delineation of key features of the retinal capillary complex including the foveal avascular zone, peripapillary vasculature, the superficial vascular complex, and the deep vascular complex.

OCT angiography (OCTA) is a functional extension of OCT that employs changes in speckle caused by blood flow as an endogenous contrast agent to image retinal microvasculature [13][14][15][16][17][18][19][20]. Unlike fluorescein angiography (FA), the current gold standard for retinal vascular imaging, OCTA does not require the intravenous injection of an exogenous contrast agent and provides higher resolution, depth resolved images of the retinal vasculature [19]. OCTA imaging of adult retinal diseases is area of active research in ophthalmology and has provided insights into the pathogenesis of many retinal diseases including age-related macular degeneration, glaucoma, and diabetic retinopathy [21][22][23][24][25][26][27][28][29]. While many pediatric diseases, such as ROP, have a vascular etiology and occur during a period of rapid retinal vascular growth [30], most OCTA systems are table top systems that cannot not be easily used to image infants in a supine position. These systems have been used to image infants, but require removing the infant from the incubator, holding the infant up to the chin rest, and applying topical anesthesia [31]. Portable, armature mounted OCTA systems (Investigational Spectralis Flex Module, Heidelberg Engineering, Heidelberg, Germany) and microscope integrated OCT systems with OCTA capabilities have been used recently to image supine patients and children during exams under anesthesia (EUAs) [32][33][34][35][36][37] but these systems are bulky and difficult to align on a non-cooperative subject. The development of a handheld OCTA (HH-OCTA) system could enable point of care, longitudinal OCTA imaging and allow for new insights into retinal vascular development and pediatric retinal diseases. Towards this goal, several groups have reported HH-OCTA systems. These systems include a contact system used to image infants during EUAs or after surgery [38,39], two non-contact OCT systems that have been used to image adult subjects [40,41], and a handheld probe designed to image the oral mucosa [42]. In this manuscript, we present preliminary results from our non-contact HH-OCTA system, including results from healthy adult volunteers, young children undergoing EUAs, and awake infants in the ICN or during clinic visits. To the best of our knowledge the images reported in this manuscript are the first HH-OCTA taken of non-sedated infants and the first HH-OCTA which show clear delineation of key features of the retinal capillary complex including the foveal avascular zone (FAZ), peripapillary vasculature, the superficial vascular complex (SVC), and the deep vascular complex (DVC).

Optical design of the HH-OCTA probe
Our group has previously reported several HH-OCT probes for various clinical applications [43][44][45] including an ultra-compact swept-source OCT probe for ICN imaging [46]. However, the microelectromechanical systems scanner mirror used to minimize weight of this probe had a limited frequency response (~150 Hz B-scans) when driven outside of resonant mode. In the new probe we used galvanometric scanners (Scannermax, Orlando, FL) to support the high speed scanning (250-500 Hz B-scans) required for OCTA [47]. The probe was designed to have a 30° field of view on the retina, ± 10 diopter refractive error correction, and the ergonomics were designed to facilitate supine imaging.
Traditionally, OCT systems employ collimated light incident on the lateral beam scanners and use a 4F relay telescope to image the scanners into the pupil. We previously reported an optical configuration using converging light on the scanner to shorten the length of the relay telescope, however this system was limited to ~16° field of view and required the use of custom lenses [48]. To improve optical performance and increase the diffraction limited field of view, we used a novel design which employs diverging light on the scanners and a longer (approximately 5F long) relay telescope to image the scanners into the pupil. Schematics for both a standard 4F and our novel "5F" retinal OCT scanner design are shown in Fig. 1. In the 4F design, the intermediate image plane is designed to be as close to telecentric as possible, while in the 5F design the diverging light on the scanner deliberately induces field curvature in the intermediate image plane. Once imaged onto the retina, the additional field curvature creates a retinal image plane that better matches the curvature of the retina minimizing defocus acros commercially NJ), and wer and the Gonc field systems model [50]. T above 0.7 ove and 5F syste scanner and th curvature and performance significant dif adult eye [51] well-establish power of the curvature, wi used to image (12. TA uses chang is also suscep most often seen CTA, operator this effect, w p that our imag d to be as symm brace was inclu s of the probe, esigned in Sol f the optomech ollimating lens for +10 D to retaining ring pectively [44]. and brace wer mplete, assem m. During EUAs, FA imaging (Retcam3, Natus Medical Incorporated, Pleasanton, CA), was performed as part of routine clinical care. Total imaging time was limited to 15 minutes for each subject. Optical power was set to less than 1.8 mW on the cornea, which is less than the ANSI Z136.1 standard for 1060 nm light [63]. All human subjects research was performed under protocols approved by the Duke University institutional review board in accordance with the Declaration of Helsinki.

Results
The high speed and ergonomic grip of the HH-OCTA probe helped facilitate regular structural OCT imaging in the ICN. During imaging, the probe was positioned vertically above the eye of the subject with the imager holding the probe by the tip using the braced position (Fig. 6). Over 63 imaging sessions (across 25 different subjects) in the ICN and clinic, the HH-OCTA probe was able to capture structural images of the optic nerve and fovea of the right eye (the first eye imaged) in 98.4% (62 of 63) of the imaging sessions. In the left eye, the probe was able to capture images in 90.5% (57 of 63) of the imaging sessions. In six imaging sessions, imaging was only performed in the right eye due to infant restlessness or pre-existing health concerns. Successful imaging was determined by the imager (who is also an expert grader) upon review of the captured images. OCTA images were qualitatively evaluated after post processing and images were labeled as high quality if capillary level vasculature or vascular pathology was visible in a significant part of the scan. During EUAs high quality OCTA scans were obtained in 100% (8 of 8) of patients. OCTA imaging was not attempted in 2 of the 14 infants imagined in the ICN due to infant restlessness or pre-existing health concerns. High quality OCTA images were obtained in 8 out of the remaining 12 subjects. In these 8 subjects, high quality OCTA images were obtained in 69.2% (27 of 39) imaging sessions. While OCTA imaging was attempted as early as 30 weeks PMA in two of these subjects, due obstruction of the eye by the tubing from a continuous positive airway pressure mask on the infant's face, we were unable to obtain OCTA images from these infants until they reached 33 weeks PMA. Eleven infants were imaged in the outpatient clinic with up to two visits each. These infants ranged from one to sixteen months corrected age. High quality OCTA images were obtained from 2 of the 11 infants imaged in clinic (both approximately 1 month corrected age). The older infants (three to sixteen months corrected age) had structural OCT but OCTA was not attempted (7 of the 11 infants). Selected volume renders and B-scans from ICN imaging are shown in Fig. 7. These images demonstrate the ability of the probe to capture clinically relevant features including the foveal depression, infant cystoid macular edema (CME), and peripheral preretinal neovascular elevations in an infant with ROP. While features such as preretinal neovascular elevations are visible in crosssectional imaging, the 3D context provided by volumetric imaging allows for enhanced visualization of 3D structures such as CME, large superficial retinal vasculature, the extent of preretinal neovascular tissues, and structural changes at the vascular/avascular junction in infants with ROP. However, as can be seen in Fig. 7(b), motion artifacts can distort surface of the retina and other anatomical features.
Initial HH-OCTA imaging to assess the OCTA capabilities of the system was performed in healthy adult volunteers lying in a supine position (Fig. 8). These images show clear visualization of the capillaries forming the FAZ, peripapillary vasculature emerging radially from the optic disc, and retinal capillaries in a region of retina nasal to the optic disc. These images also demonstrate the difference between artifacts caused by saccades and hand motion. Saccades manifested as narrow streaks on the angiograms with sharp discontinuities between the vasculature on each side of the artifact (red arrows in Fig. 8) [55,64]. In many of the OCTA images acquired, there were also broader artifacts with wavy but continuous vasculature (yellow arrows in Fig. 8). Due to their presence in images of cooperative, fixating adults, we believe that these artifacts result from washout of the OCTA signal caused by the operator's hand motion causing bulk decorrelation of the background tissue.  EUAs (Fig. 9) s that HH-OCT isible on FA wi with a history gions of the re g. 9(e)). Separ a network of g)). Since  OCTA images and while a tracking system could allow for compensation for some of the motion, quite often this motion is significant enough that it requires the operator to completely reset the position of the probe, limiting the utility of tracking. Since the exam with the HH-OCTA probe is non-invasive (it does not require the use of an eyelid speculum or topical anesthetic drops, and it uses non-visible light unlike a traditional indirect retinal exam) we found that many young infants remain calm throughout the exam and some will even fall asleep. While their gaze frequently moves, when they are calm their gaze will eventually remain still for short periods. Instead of including alignment aids or tracking we focused on patient and imager comfort by optimizing the probe's ergonomics for supine imaging. This facilitates sustained imaging where the imager is able to quickly make adjustments for eye motion. Real time display of the OCT data allows for the imager to identify when the infant's gaze has stabilized and the longer OCTA scans can be taken. This approach allowed us to take OCTA acquisitions which were three to six seconds long. However, we observed that older infants had greater baseline movement during the HH-OCTA exams. For example, 6 to 9 month old infants were substantially more active and difficult to image than a newborn. While OCTA is often not possible in these active infants, the ergonomics and high speed of the system enables consistent structural OCT imaging.

Conclusion
We developed an optically novel, ergonomic, 200 kHz HH-OCTA probe optimized for supine, portable, non-contact imaging. The probe weighs 700g, has −10D to +10D refractive error correction, and a 30° diffraction limited field of view. HH-OCTA imaging was performed in healthy adult volunteers, pediatric patients undergoing exams under anesthesia, and awake infants in the ICN/clinic. The OCTA images reported in this manuscript are the first HH-OCTA taken of non-sedated infants and the first HH-OCTA images to show depthresolved retinal microvasculature and microvascular abnormalities. These images show vascular abnormalities in close proximity to pathological structures and we believe that further imaging with this probe will lead to new insights into the development and pathology of the pediatric retina.