Abstract
Background:
Misidentifying parathyroid glands (PGs) during thyroidectomies or parathyroidectomies, could significantly increase post-operative morbidity. Imaging systems based on near-infrared autofluorescence (NIRAF) detection can localize PGs with high accuracy. These devices however depict NIRAF images on remote display monitors, where images lack spatial context and comparability with actual surgical field-of-view (FOV). In this study, we designed an Overlay Tissue Imaging System (OTIS) that detects tissue NIRAF and back-projects the collected signal as a visible image directly onto the surgical FOV instead of a display monitor, and tested its ability for enhancing parathyroid visualization.
Study Design:
The OTIS was first calibrated with a fluorescent ink grid and initially tested with parathyroid, thyroid and lymph node tissues ex vivo. For in vivo measurements, the surgeon’s opinion on tissue-of-interest was first ascertained. After the surgeon looked away, the OTIS back-projected visible green light directly onto the tissue-of-interest, only if the device detected relatively high NIRAF as observed in PGs. System accuracy was determined by correlating NIRAF projection with surgeon’s visual confirmation for in-situ PGs or histopathology report for excised PGs.
Results:
OTIS yielded 100% accuracy when tested ex vivo with parathyroid, thyroid and lymph node specimens. Subsequently, the device was evaluated in 30 patients who underwent thyroidectomy and/or parathyroidectomy. 97% of exposed tissue-of-interest were visualized correctly as PGs by the OTIS without requiring display monitors or contrast agents.
Conclusion:
While OTIS holds novel potential for enhancing label-free parathyroid visualization directly within the surgical FOV, further device optimization is required for eventual clinical use.
Keywords: Parathyroid gland visualization, surgical guidance, thyroidectomy, parathyroidectomy, near infrared fluorescence, fluorescence projection
PRECIS
A near infrared autofluorescence-based overlay imaging system was developed for improving parathyroid visibility directly in the surgical field without requiring display monitors or contrast agents. The device detects near-infrared signal from parathyroid tissue and projects a visible image back onto it and enhances its visibility for surgeons.
INTRODUCTION
Inaccurate identification of parathyroid glands (PGs) during thyroidectomies, parathyroidectomies or combined surgeries result in long term post-operative implications for patients (1-3). Accidental damage or excision of healthy PGs cause permanent hypocalcemia in about 12% of patients following thyroidectomies (4). Conversely, 30% of parathyroidectomies required reoperation due to failure in removal of all diseased PGs (5). Preoperative localization of diseased parathyroid glands are performed predominantly with Sestamibi scintigraphy in conjunction with ultrasound imaging, computed tomography (CT) or magnetic resonance imaging (MRI) (6). While Sestamibi scintigraphy with ultrasound imaging have sensitivity ranging between 40 – 70% (6-8), costs associated with CT or MRI scanning limit its routine use. Surgeons typically rely on visual inspection and surgical experience to identify PGs intraoperatively during head and neck surgical procedures. This can be problematic for resident trainees, low-volume center surgeons, and occasionally even for highly experienced surgeons (9). As a result surgeons tend to confirm identity of parathyroid tissues utilizing frozen section analysis, which is however an invasive technique that adds to time and costs of the surgical procedure. Intraoperative parathyroid hormone (IOPTH) assay is another valuable technique that informs the surgeon if there is a need to explore for additional diseased (hypercellular) PGs after removing one diseased gland, thereby proving beneficial in confirming removal of all hyperactive PGs during parathyroidectomies (10, 11). However this assay requires periodic blood sampling (12) and is rarely used during thyroidectomies. Since these techniques cannot be used to localize healthy PGs during thyroidectomies, there is a dire need for a reliable, real-time, non-invasive tool for identifying PGs, regardless of whether the glands are healthy or diseased, during all neck surgeries – including thyroidectomies and parathyroidectomies.
Our research group originally discovered near-infrared autofluorescence (NIRAF) in PGs to be significantly elevated as compared to adjacent neck tissues, following which we developed a non-invasive, label-free optical method using a hand-held surgical probe that performed point-based measurements for reliable parathyroid identification with 97% accuracy, irrespective of disease state (13, 14). The technology was then translated to a user-friendly clinical prototype ‘PTeye’ that got recently FDA-approved for label-free parathyroid identification (15, 16). However point-based measurements lacks the ability to provide spatial information regarding PGs. In contrast, an imaging system can acquire valuable spatial information and thus aid in visualizing PGs in context with adjacent anatomical structures. To address this need, we had earlier developed an imaging system that detects tissue NIRAF, allowing the user to view the entire surgical field and localize PGs with 100% accuracy (17). Since then various groups have evaluated the potential of parathyroid localization with using commercial near infrared (NIR) imaging systems such as Fluobeam (Fluoptics, Grenoble, France) and Hamamatsu PDE systems (Hamamatsu Photonics, Hamamatsu, Japan) (18-22). However when using intraoperative imaging modalities – including NIR imaging systems, it could be challenging to effectively correlate images seen on a display monitor with the anatomy observed directly under a surgeon’s field-of-view (FOV) resulting in erroneous image interpretations (23-25). In addition, staring at remote image displays and investing time for image output lessen the effectiveness of imageguided surgery (26, 27). These challenges could be offset by optimizing design ergonomics and image visualization techniques (24, 28).
Recent advances in improving intraoperative image visualization and co-registration involves virtually merging the acquired images with the actual surgical FOV. This merging has been investigated with microscope oculars, semi-transparent mirrors or goggles worn by the surgeon (29-31). A more intuitive approach would be to project the image directly onto the surgical FOV (see Figure 1). Image projection onto skin is already utilized in commercial devices such as VeinViewer and Accuvein, which relies on NIR light absorption by deoxygenated hemoglobin in vein (32). The concept of NIRAF-based image overlay was first demonstrated by Sarder et al. and subsequently investigated in various animal models (33-35). However the motivation of those studies were restricted to tumor margin guidance and sentinel lymph node mapping, while heavily depending on exogenous contrast agent administration to boost NIRAF signal. Our group recently developed a modular NIRAF-based Overlay Tissue Imaging System (OTIS) for wide-field intraoperative surgical guidance (36). This portable device is designed to collect real-time optical images of the tissues, process the signal and back-project a visible image directly onto the surgical FOV in real-time, thus eliminating the need for a remote display monitor. In this manuscript, we report on the capability of OTIS to enhance NIRAF visualization of PGs for the surgeon’s naked eye directly in the surgical FOV without relying on remote display monitors or exogenous contrast agents in real-time.
Figure 1.
Comparison between conventional near infrared autofluorescence (NIRAF) imaging and tissue NIRAF overlay imaging. Conventional NIRAF images are typically displayed as grey scale NIR images on a remote display that may lack comparability with the actual surgical site. Tissue NIRAF overlay imaging could provide the same information by image projection directly onto surgical site thus offering improved spatial context. This also enables the surgeon’s line-of-focus to stay in the surgical field without being diverted to a display monitor.
MATERIALS AND METHODS
Device description of Overlay Tissue Imaging System (OTIS)
The OTIS comprises of (a) a NIR 785 nm diode laser (Innovative Photonics Solutions, Monmouth Junction, NJ), (b) a NIRAF image collection unit, (c) a data processing laptop and (d) a visible light projection unit (Figure 2A). The NIR diode laser was designed to illuminate a surgical FOV ranging from 5 cm × 5 cm (irradiance = 11.5 mW/cm2) to 15 cm × 15 cm (irradiance = 0.6 mW/cm2). The NIRAF image collection unit consists of NIR complementary metal oxide semiconductor (CMOS) camera (Basler AG, Ahrensburg, Germany) along with focusing optics and filters. The maximum spatial resolution for the NIRAF image collection unit in this system is 250 μm for a surgical FOV of 15 cm × 15 cm (36). The visible light projection unit relies on a high-lumen light-emitting diode projector (AAXA Technologies, Irvine, CA). A color CMOS camera (Basler AG, Ahrensburg, Germany) is additionally mounted for capturing images seen with the naked eye. The NIRAF image collection and visible light projection units are attached to a ball mount that can be positioned at any required angle (Figure 2B). The mount is connected to a double articulated arm attached to a portable cart that also holds the near infrared laser and the laptop where image processing occurs through a user-interface designed with LabVIEW software (National Instruments, Austin, Texas)
Figure 2.
(A) Schematic of the imaging-projection unit of Overlay Tissue Imaging System (OTIS). The unit comprises (i) a 785 nm diode laser, (ii) a near infrared autofluorescence (NIRAF) image collection unit – a near infrared (NIR) camera with focusing and long pass filter optics, (iii) a data processing laptop and (iv) a visible light projection unit. A color camera is additionally integrated to capture the projected image. (B) The imaging-projection unit is attached to ball mount which in turn is connected to a double articulated arm supported by a portable cart. A disposable sterile handle (green) is inserted into a slot designed on the arm, which permits the surgeon to conveniently position the imaging unit at any angle above the surgical field. CMOS, complementary metal oxide semiconductor.
Workflow with OTIS
For utilizing OTIS, the surgeon first positions the imaging unit above the required FOV using a disposable sterile handle. After illuminating the required FOV with 785 nm diode laser, tissue fluorescence signal is detected by the camera in NIRAF image collection unit. Raw NIRAF images are then relayed to the laptop for real-time processing using a customized algorithm in LabVIEW software. The algorithm first selects a user-defined region within the surgical FOV and then amplifies NIRAF signal by real-time feature extraction, while reducing ambient noise associated with stray operating room lights and background fluorescence.
After real-time feature extraction, the processed image is sent to the visible light projection unit and then converted here to a visible green intensity map, following which it is projected onto the surgical FOV. The visible light projection was performed only if NIRAF signal-to-background ratio was 1.5 or higher in the acquired NIR image. This threshold was set to ensure that visible light projection overlay was performed only for parathyroid tissue and not for non-parathyroid regions. The NIR camera and the projector unit are aligned such that the collected NIRAF image and projected visible image spatially overlap accurately. Images are continuously processed and projected onto the target FOV at a rate of 4 frames per second, allowing real-time, dynamic visualization of NIRAF information at the target site. The OTIS is designed with projection accuracy that lies within 0 to 1 mm (36), which is well over the required resolution to aid in visualizing normal PGs (2 – 4 mm diameter).
Ex vivo validation of OTIS
Spatial accuracy of OTIS was first calibrated using a grid phantom sketched with NIR fluorescent ink on white paper (Figure 3A). Alignment of the projected image with the actual sketched ink grid was evaluated for any spatial mismatch (Figure 3B and 3C). Orientation of the NIRAF image collection and visible light projection unit were adjusted accordingly to minimize mismatch and ensure accurate co-registration of projected image with the sketched ink grid. This step was performed prior to each OTIS measurement to calibrate image alignment.
Figure 3.
Ex vivo characterization and testing of Overlay Tissue Imaging System (OTIS). (A) White light image of grid phantom sketched with near infrared (NIR) fluorescent ink. (B) NIR image of the grid phantom. (C) Corresponding visible green light overlay onto the original target site indicating high spatial accuracy. (D) White light image of parathyroid adenoma, thyroid and normal lymph node tissues. (E) NIR image depict relatively strong near infrared autofluorescence (NIRAF) signal only from the two parathyroid adenomas. (F) Visible green light is overlaid accurately only over the two parathyroid adenoma specimens, while thyroid and lymph node specimens received no green overlay.
Frozen tissues obtained from the Vanderbilt Tissue Bank (Vanderbilt University Medical Center) comprising of two specimens each of parathyroid adenomas, normal thyroid and normal lymph nodes were first utilized for validating the ex vivo performance of OTIS. The frozen tissues were first thawed and then placed randomly on a non-reflective substrate, at a distance of 35 cm below the OTIS. NIRAF images were acquired with a 300 milliseconds exposure time, while the entire workflow of NIRAF signal collection, image processing and back-projection of visible green image took not more than two minutes. The color CMOS camera captured color images of tissues initially without and later with visible light overlay.
Intraoperative Testing of OTIS
Thirty patients undergoing parathyroidectomy and/or thyroidectomy were recruited for this study at the Vanderbilt University Medical Center after approval from the Institutional Review Board (IRB). Adult patients above the age of 18 years undergoing endocrine surgery due to thyroid and/or parathyroid disease were included for this study. Written informed consent was obtained from all enrolled patients prior to surgery. Measurements were excluded from the study (i) if no histology was available for the tissue-of-interest when identified with low confidence by the surgeon or (ii) if the operation room (OR) lights were not turned completely off.
Prior to each procedure, image co-registration of the OTIS was evaluated using NIR fluorescent ink grid as described earlier. For the purpose of parathyroid visualization with OTIS, a FOV measuring 5 cm × 5 cm was considered adequate as surgical incision length for standard thyroidectomy and parathyroidectomy typically ranges between 4 – 6 cm (37). Once the PGs were exposed, the confidence level (high, medium, or low) of the surgeon in visually identifying each PG was recorded. A visible white grid was first projected onto the surgical FOV to aid the surgeon in positioning the OTIS towards the region of interest. The surgeon then positioned OTIS approximately 35 cm above the surgical FOV using a disposable sterile handle (attached as seen in Figure 2B), without affecting sterility of the surgical work-flow. Subsequently all OR lights were turned off and surgical headlights directed away to minimize light interference. NIRAF images were collected, processed, and projected directly as visible images onto the surgical FOV as described in previous section. The surgeon looked away and was blinded to the image projection of OTIS so as to not affect patient outcome. Each in vivo measurement with OTIS took not more than two minutes that included the entire process of capturing NIRAF image from region of interest and projecting it back as a visible color image directly onto the surgical site. Visual confirmation was employed for identifying in-situ healthy PGs during thyroidectomies as these are not typically removed during surgery, while frozen biopsy and histopathology reports were used for confirming identities of tissues excised during parathyroidectomies. Tissue sites with a low surgical confidence level were excluded from analysis, unless there was available histology from that tissue.
Statistical Analysis
NIRAF signal was first normalized to the background signal to obtain NIRAF signal-to-background ratio and presented as mean ± standard error. Two-tailed student’s t-tests for unequal variance were used to assess statistical significance, with values of p<0.05 being considered significant.
RESULTS
The feasibility of real-time intraoperative overlay tissue imaging system (OTIS) to enhance parathyroid visualization was investigated in this study. The results demonstrate that NIRAF signal from PGs could be successfully projected as visible image directly onto the surgical field of view (FOV) with high accuracy, without requiring remote display monitors
Ex vivo validation of OTIS
For the grid phantom sketched with NIR fluorescent ink (Figure 3A), the OTIS first captured a NIRAF image of the inked grid (Figure 3B) and then subsequently projected a visible green image (Figure 3C) that was well-aligned spatially with the position of the grid phantom. When tested with tissue specimens ex vivo (Figure 3D), OTIS achieved 100% accuracy in parathyroid identification – 2/2 parathyroid tissues (100% sensitivity) and 4/4 non-parathyroid tissues – thyroid, lymph nodes (100% specificity). NIRAF images captured by OTIS for tissue specimens indicated higher intensities for parathyroid adenoma specimens as compared to the normal thyroid and lymph node tissues (Figure 3E). Based on the detected NIRAF signal, OTIS projected visible green light only on parathyroid specimens and none on the non-parathyroid tissues as seen in Figure 3F.
The projection overlay with OTIS is dynamic in nature – as the target (grid phantom or tissue specimens) shifts, the projected image overlay also shifts accordingly with high sensitivity. A demonstration of NIR fluorescence-based overlay imaging performed initially with a grid sketched with NIR fluorescent ink and subsequently with parathyroid, thyroid and lymph node tissues ex vivo can be seen in Video 1. The delay or lag of the image overlay in relation to the target is less than 2 seconds.
Intraoperative testing of OTIS
For this study, 75 measurements were acquired with OTIS from regions of interest in 30 patients undergoing parathyroidectomy and/or thyroidectomy. Fifteen of these patients were diagnosed with hyperparathyroidism (primary or secondary), while twelve patients suffered from thyroid disease and three patients had concurrent parathyroid-thyroid disease (Table 1). Out of the 75 measurements obtained with OTIS, 4 were excluded due to interference from OR lights that were not completely switched off. It must be emphasized that as described earlier, the OR lights were meant to remain off during the measurements. However, in these 4 glands, the OR lights accidentally remained on, which interfered with NIRAF measurements from the tissue in view. Thus, NIRAF signal from parathyroid could not be detected due to OR light interference, leading to exclusion of these measurements. In addition to those 4 glands, measurement from another one gland was omitted due to system error, while the remaining 70 were eventually considered for further data analysis.
Table 1.
Overview of Patient Demographics, Diseases States, Tissue Histopathology, and Corresponding Intraoperative Assessment with Overlay Tissue Imaging System
| Case type, disease, patient no. | Age, y | Sex | BMI, kg/m2 | Surgeon’s opinion of parathyroid |
Parathyroid histopathology |
Surgeon’s confidence |
Parathyroid in vivo NIRAF* |
OTIS overlay |
|---|---|---|---|---|---|---|---|---|
| Thyroidectomy | ||||||||
| Benign thyroid goiter | ||||||||
| 4 | 55 | F | 29.9 | Healthy | NA | High | + | Y |
| Healthy | NA | High | + | Y | ||||
| Healthy | NA | High | + | Y | ||||
| Healthy | NA | High | ++ | Y | ||||
| 8 | 62 | M | 25.2 | Healthy | NA | High | ++ | Y |
| Healthy | NA | High | ++ | Y | ||||
| 15 | 59 | F | 41.3 | Healthy | NA | High | ++ | Y |
| 17 | 58 | F | 32.3 | Healthy | NA | High | ++ | Y |
| Healthy | NA | High | ++ | Y | ||||
| Healthy | NA | High | ++ | Y | ||||
| 28 | 50 | F | 36.3 | Healthy | NA | High | ++ | Y |
| Healthy | NA | High | + | Y | ||||
| Graves’ disease | ||||||||
| 7 | 51 | F | 26.6 | Healthy | NA | High | + | Y |
| Healthy | NA | High | + | Y | ||||
| Healthy | NA | High | + | Y | ||||
| Healthy | NA | High | + | Y | ||||
| Papillary thyroid cancer | ||||||||
| 3 | 70 | F | 28.5 | Healthy | NA | High | ++ | Y |
| Healthy | NA | High | ++ | Y | ||||
| 6 | 32 | F | 25.1 | Healthy | NA | High | + | Y |
| Healthy | NA | High | + | Y | ||||
| 10 | 55 | M | 26.6 | Healthy | NA | High | ++ | Y |
| Healthy | NA | High | ++ | Y | ||||
| 13 | 59 | F | 23.2 | Healthy | NA | High | + | Y |
| Healthy | NA | High | + | Y | ||||
| 20 | 51 | M | 32.2 | Healthy | NA | High | +++ | Y |
| 25 | 29 | F | 20.5 | Healthy | NA | High | ++ | Y |
| Healthy | NA | High | - | N | ||||
| Healthy | NA | High | ++ | Y | ||||
| Healthy | NA | High | ++ | Y | ||||
| Parathyroidectomy | ||||||||
| Primary hyperparathyroidism | ||||||||
| 1 | 66 | F | 26.1 | Healthy | NA | High | ++ | Y |
| Diseased | Hypercellular (adenoma) | High | ++ | Y | ||||
| Healthy | NA | High | +++ | Y | ||||
| Diseased | Benign thyroid | Low | - | N | ||||
| 9 | 70 | F | 22.8 | Diseased | Hypercellular | High | ++ | Y |
| Diseased | Hypercellular | High | ++ | Y | ||||
| Diseased | Hypercellular | High | ++ | Y | ||||
| 12 | 67 | F | 47.8 | Diseased | Hypercellular (adenoma) | High | ++ | Y |
| Healthy | NA | High | ++ | Y | ||||
| 14 | 39 | F | 38.1 | Diseased | Hypercellular | High | ++ | Y |
| Diseased | Normocellular | High | +++ | Y | ||||
| Diseased | Hypercellular | High | ++ | Y | ||||
| 16 | 64 | F | 53.3 | Healthy | NA | Moderate | + | Y |
| Healthy | NA | Moderate | ++ | Y | ||||
| 18 | 60 | F | 38.1 | Healthy | NA | High | ++ | Y |
| Healthy | NA | High | +++ | Y | ||||
| Diseased | Hypercellular (adenoma) | High | ++ | Y | ||||
| 19 | 61 | M | 25.1 | Diseased | Parathyroid carcinoma | High | - | N |
| 22 | 52 | F | 30.8 | Diseased | Hypercellular (adenoma) | High | ++ | Y |
| Healthy | NA | High | +++ | Y | ||||
| 23 | 74 | F | 20.8 | Diseased | Hypercellular | High | + | Y |
| Diseased | Hypercellular | High | ++ | Y | ||||
| Diseased | Hypercellular | High | ++ | Y | ||||
| 24 | 43 | M | 31 | Diseased | Normocellular | Moderate | ++ | Y |
| Diseased | Hypercellular | High | +++ | Y | ||||
| 26 | 55 | F | 30.6 | Diseased | Normocellular | High | ++ | Y |
| Healthy | NA | High | ++ | Y | ||||
| Healthy | NA | High | ++ | Y | ||||
| 27 | 67 | F | 32.1 | Diseased | Hypercellular | High | ++ | Y |
| Diseased | Hypercellular | High | +++ | Y | ||||
| Healthy | NA | High | + | Y | ||||
| Primary hyperparathyroidism (MEN-1) | ||||||||
| 5 | 57 | M | 25.7 | Diseased | Hypercellular | High | +++ | Y |
| Diseased | Hypercellular | High | ++ | Y | ||||
| Recurrent hyperparathyroidism | ||||||||
| 21 | 65 | F | 25.2 | Diseased | Hypercellular (adenoma) | High | ++ | Y |
| Secondary hyperparathyroidism | ||||||||
| 11 | 46 | F | 36.8 | Diseased | Hypercellular | High | ++ | Y |
| Diseased | Hypercellular | High | ++ | Y | ||||
| Thyroidectomy combined with parathyroidectomy | ||||||||
| Primary hyperparathyroidism with benign thyroid goiter | ||||||||
| 2 | 73 | F | 28 | Diseased | Hypercellular (adenoma) | High | +++ | Y |
| 29 | 57 | F | 26.2 | Diseased | Hypercellular (adenoma) | High | ++ | Y |
| Healthy | NA | High | +++ | Y | ||||
| Healthy | NA | High | ++ | Y | ||||
| 30 | 35 | F | 24.5 | Diseased | Hypercellular (adenoma) | High | + | Y |
Signal-to-background ratio grading: - [<1.5]; + [1.5 to 2.2]; ++ [2.3 to 4.9]; +++ [>5]. MEN-1, multiple endocrine neoplasia type 1; NA, not applicable; NIRAF, near-infrared autofluorescence; OTIS, Overlay Tissue Imaging System.
Figures 4 depicts OTIS images acquired from the surgical FOV of 4 patients, where the left column (Figures 4A – 4D) display white light images akin to what is seen by the surgeon’s naked eye (Figure 4A – 4D), prior to NIRAF image capture with OTIS. The right column of images (Figures 4E – 4H) show white light images of the same surgical site in the corresponding patients after OTIS projects the NIRAF image onto the surgical FOV with visible green light. The overlay in green color provided enhanced visual contrast for PGs against adjacent tissue structures directly at the surgical site. It should be noted that intensity of the green overlay directly correlated with NIRAF signal intensity collected from the PGs. In this study, 45 healthy PGs had an averaged NIRAF signal-to-background ratio of 4.51 ± 1.24, which was not significantly different from that of 24 diseased PGs (adenomas, multi-glandular hyperplasia and carcinoma) of 4.81 ± 0.80. Adjacent neck tissues (thyroid, muscle, fat) had an averaged NIRAF signal-to-background ratio of 1.03 ± 0.02, which was significantly lower than both normal and diseased parathyroid glands (p<0.05).
Figure 4.
Intraoperative results with Overlay Tissue Imaging System (OTIS) during thyroidectomies and parathyroidectomies. White light images of healthy parathyroid glands exposed in thyroidectomies for (A) benign multinodular goiter and (B) papillary thyroid carcinoma. White light images of diseased parathyroid glands – (C) parathyroid adenoma and (D) hyperplastic parathyroid gland from multi-glandular hyperplasia – exposed during parathyroidectomies. (E – H) Corresponding images of the same regions as in Figure 4A – 4D with near infrared autofluorescence (NIRAF) projection overlay, where the parathyroid glands are overlaid with visible green light – enhancing its visibility to the surgeon’s naked eye directly in the surgical field. Note that the other adjacent soft tissues in neck do not receive projection overlay due to weak NIRAF signal relative to parathyroid tissue. Parathyroid glands are indicated with yellow arrow in figure. Rectangular white grid projection (indicated with white arrow) enables the surgeon to position the imaging-projection unit over region of interest.
Out of the 70 device measurements considered for data analysis, OTIS was able to enhance visualization at 67 out of 70 regions of interest across thirty patients. Among these three tissue sites, two turned out to be PGs that had low NIRAF signal compared to the background and hence did not receive fluorescence projection overlay by OTIS. Measurements from the remaining one tissue site provided a noteworthy finding as observed in Patient 1 (see Table 1), where a suspect parathyroid candidate assessed with low confidence by the surgeon was imaged with OTIS. Since no NIRAF signal was detected, no green light was overlaid onto the tissue candidate. Subsequent frozen section analysis confirmed that the specimen was comprised of only benign thyroid tissue, highlighting the specificity of OTIS. Therefore in terms of detection rate, OTIS managed to enhance visual contrast for 97% of PGs (67/69 PGs) directly in the surgical FOV without requiring any contrast agents.
DISCUSSION
In this manuscript, we present a projection overlay system called OTIS that was designed to guide surgeons for improved visualization of PGs directly in the surgical field. The findings of this study demonstrated the applicability of OTIS for enhanced parathyroid visualization in an intraoperative setting. The results reveal that OTIS could detect 97% of parathyroid glands in vivo without requiring remote display monitors or exogenous contrast agents, thus highlighting OTIS as a novel tool that could potentially enhance parathyroid visualization directly within a surgeon’s field-of-view (FOV). This system could thus eliminate erroneous image interpretation, supplement visual inspection and potentially reduce surgical complications.
Reliable intraoperative localization of parathyroid glands, irrespective of disease state could minimize patient morbidity by reducing incidences of postoperative hypocalcemia or repeat surgeries. Current clinical imaging modalities such as Sestamibi scintigraphy and ultrasound imaging, can only aid in preoperative localization of diseased parathyroid glands. Therefore a surgeon typically relies on visual inspection to avoid damage/excision of healthy PGs or ensuring complete removal of diseased PGs in an intraoperative setting. The subjective nature of visual inspection and variability in surgical experience is a deterrent in correctly identifying PGs. This was the reason why discovery of NIRAF in PGs by Paras et al. (13) led to a rapid emergence of label-free NIRAF based imaging modalities being considered for objectively guiding surgeons in accurate identification or localization of PGs (14, 17, 20-22). However these imaging systems typically depict grey scale NIRAF images on remote display monitors, which provides no spatial context of PGs in relation to adjacent structures. This may not be comparable to the actual surgical site and may lead to interpretive errors. In comparison, OTIS is distinct in projecting a processed image that highlights strong NIRAF regions such as PGs directly onto the surgical FOV. Since PGs are visibly lit up directly within the surgical FOV, a more accurate spatial context of adjacent structures in relation to PGs can be observed without diverting the line-of focus to a remote display monitor.
As seen in Figure 4A to 4D, it could be challenging for surgeons to distinguish PGs from its adjacent surroundings with the naked eye, due to the homogeneous appearance of tissues in the surgical FOV. In stark contrast, image projection by OTIS in visible green light enhanced visibility for both healthy and diseased PGs (Figure 4E – 4H). The visible contrast is further augmented because adjacent structures in the surgical FOV such as thyroid gland, fat and muscle were not overlaid in green, due to the relatively lower normal NIRAF intensity compared to PGs. In light of these findings, it must be highlighted that OTIS can project images within 0 to 1 mm accuracy that yields a high degree of spatial precision as evidenced in Figure 3A and 3C, at an imaging distance of 35 cm from the surgical FOV (36). This was further validated with ex vivo tissue specimens (Figure 3D and 3F), where only the 2 parathyroid adenomas were accurately overlaid in visible green, while the remaining tissues were not. Subsequently, Figure 4 demonstrated the intraoperative efficacy of OTIS in vivo enhancing visibility in 97% of PGs, distinguishing these from surrounding tissues.
It must however be considered that direct intraoperative visualization of PGs does not usually pose a major problem for experienced endocrine surgeons. This was clearly evident during data interpretation as our surgeon correctly identified 66 of 70 tissues (94.3%) in neck with high confidence. We should also point out that our present study design involved a single surgeon who is highly experienced. Therefore interpretation of benefits from a device such as OTIS would require a larger study design involving multiple surgeons with varied experience, skill-set and patient-volume since these parameters determine surgical outcomes eventually (38-41). Nonetheless, accidental damage and devascularization of healthy PGs is a key challenge faced by even experienced surgeons, especially during radical neck surgeries that involve lymph node dissection. In such scenarios, OTIS can highlight healthy PGs directly in the surgical field, enabling surgeons to carefully maneuver dissection and avoid damage to PGs or its blood supply. Visualizing with OTIS can also be useful for scanning an excised thyroid specimen to look for healthy parathyroid tissue that may have been accidentally removed so that the surgeon can then autotransplant the parathyroid tissue back in the patient to prevent post-operative hypocalcemia. It must however be borne in mind that damage to PGs or its blood supply is a more common cause for post-operative hypocalcemia following thyroid surgeries, as accidental removal of healthy PGs is not as frequent. In such scenarios, surgeons would benefit from an objective modality that can evaluate parathyroid vascularity and/or viability as well, to minimize the risk of post-operative hypocalcemia. Although OTIS can aid the surgeon in being cautious while dissecting around healthy PGs, the technique by itself cannot provide insight regarding the vascularity or viability of the visualized PGs. In recent times, optical techniques such as indocyanine green (ICG) based fluorescence angiography (42, 43) or laser-speckle imaging (44) have demonstrated potential for assessing parathyroid perfusion or viability, and could therefore be used complementarily with NIRAF-based modalities such as OTIS.
With regard to detecting diseased/hyperfunctioning PGs, current imaging modalities typically utilize Sestamibi scans to aid in preoperatively localizing adenomas, but this technique has a limited role in detecting multiglandular hyperplasia. Even then the gland location could shift during surgical dissection and may not match with preoperative scans. In such scenarios OTIS can be used for intraoperatively identifying diseased PGs as depicted in Figure 4G and 4H. Since OTIS can visualize with a spatial resolution of 250 μm, it can detect PGs as small as 2 mm in diameter that typically get missed using current methods. As a result, OTIS can prove useful for visualizing all types of PGs, while providing surgical guidance for ectopic glands and reoperative parathyroidectomies.
While OTIS presents a novel feature of projecting the location of PGs directly within the surgical FOV, it must be noted that margins of the projected images did not precisely match that of parathyroid specimens, since a 2-dimensional image is being projected over a 3-dimensional structure. Despite this error, the current design parameters of OTIS suffice for simple parathyroid visualization as the final overlay was capable of localizing PGs amidst other tissues ex vivo with 100% accuracy. This iterates that while OTIS performs optimally in guiding surgeons to identify parathyroid tissue in his/her surgical FOV, the device should be further optimized for surgeries that may require higher precision. While analyzing the performance of OTIS, it should be taken into account that all parathyroid candidates included in this study were exposed prior to measurement. The present system design of OTIS therefore allows to confirm the identity of a suspect parathyroid candidate that is surgically exposed but may be limited in localizing a ‘missing’ parathyroid. While NIRAF signal can penetrate down to a few millimeters deep in soft tissue, it must be reemphasized that identifying/localizing PGs on the basis of NIRAF detection would additionally depend on the optical properties of tissues that lies above the suspect parathyroid candidate. In that respect, while it may be possible to visualize PGs below fatty layers as demonstrated in the findings of Kim et al. (21, 45), the same principle will not be applicable for localizing deep seated or intra-thyroidal parathyroid glands as the optical properties of thyroid tissues is significantly different from that of fatty layers. In addition, since the studies by Kim et al. did not precisely quantify the thickness of layers involved, further studies will be required to investigate depth-related detection limit of NIRAF signals from parathyroid using OTIS, which may thus aid in localizing PGs situated deeply. While portability and flexibility of the OTIS setup can ensure a smooth translation into the surgical workflow, interference from ambient OR lights currently affect functionality of OTIS and other NIR imaging systems. It must be noted that data from four glands were excluded from the study because OR lights that still remained on accidentally during those measurements masked NIRAF signal from the parathyroid candidates. This can however be potentially addressed in future iterations of OTIS by subtracting surgical OR light noise. Another aspect regarding the present system design of OTIS is that the motion of the image overlay is delayed in relation to that of the target by less than 2 seconds during dynamic projection. This time-delay can be minimized further by employing more rapid image processing algorithms in OTIS to ensure a more optimized dynamic image overlay projection. It should also be mentioned that the current user-interface of OTIS would require further simplification to ensure ease-of-use for the surgical personnel, akin to VeinViewer and Accuvein (32, 46). For this purpose, OTIS can be further designed with a more intuitive user-interface in a manner similar to the PTeye – a user-friendly clinical prototype for label-free parathyroid identification – that was translated from the original research-grade system (15). In terms of device safety, the current design of OTIS poses no risk to patients, as NIRAF from PGs can be visualized with a excitation power density of 0.6 mW/cm2, which is lower than 11 mW/cm2 that is reportedly used for parathyroid gland imaging with exogenous contrast (47).
Since the surgeon remained blinded in our study design, it is currently unknown on how OTIS could potentially affect patient outcome. However other modalities that have relied on NIRAF detection for localizing PGs like OTIS, have presented promising preliminary results. Benmiloud et al. recently demonstrated that utilizing a NIR imaging system for parathyroid detection minimized postoperative hypocalcemia in thyroidectomies (20). The findings suggest that OTIS, in a manner similar to NIR imaging devices, could reduce these complications and improve patient outcomes. Another highlight of our study was the specificity of OTIS which potentially allows to exclude false positive candidates assumed to be PG. As described earlier, OTIS displayed no NIRAF signal for a tissue candidate identified by the surgeon as parathyroid adenoma that was eventually confirmed to be benign thyroid tissue. In that aspect, NIRAF-based modalities such as OTIS can be effective in reducing the number of frozen sections and related costs required for confirming PGs in real-time. This in turn could aid both surgeons and patients by minimizing the wait-time of 20 minutes that is typically associated for frozen section analysis, which again helps in cutting expenses associated with additional anesthesia administration (48). The benefits of technology such as OTIS in hospitals/medical centers would in turn depend on the volume of surgeries done and the experience of the surgeon. In this regard, a device such as OTIS would mostly be valuable for (i) early career surgeons with less experience at high-volume centers and (ii) established surgeons at low-volume centers, since surgeons with less years of experience or low-volume surgeons are associated with higher complication rates (49-51). As with other surgical guidance devices such as intraoperative nerve monitoring systems, a device like OTIS could also be a useful educative tool for training surgical residents in intraoperative parathyroid identification. In addition to label-free parathyroid visualization, OTIS can also be utilized in conjunction with suitable contrast agents for fluorescence image projection that holds potential for (i) assessing tissue vascularity, (ii) tumor margin guidance and (iii) sentinel lymph node detection, without requiring a display monitor (33-36, 42). These aspects render OTIS as a multi-functional device that could be considered as a cost-effective investment for different type of operations by multiple surgeons. In terms of cost-effectiveness, once the use of a modality such as OTIS in the OR becomes more widespread, it would lead to mass production of similar devices, eventually resulting in affordable costs for the end-user. In terms of overall impact of this technology, future outcome studies are necessary to investigate and assess whether OTIS alongside other NIRAF-based modalities is valuable or not for a surgeon, in terms of lowering the rates of post-surgical complications and related emergency department visits (52), cutting healthcare expenditure (53), and considerably limiting post-operative litigations (54).
CONCLUSIONS
This manuscript presents OTIS, a device that is capable of NIRAF-based image overlay directly onto the surgical field. While the novelty and portability of OTIS can highly benefit surgeons in improving parathyroid visualization during head and neck surgeries, further iterations of the device would allow OTIS to be seamlessly integrated into the current surgical workflow during thyroidectomies and parathyroidectomies. Success implementation of such a device is an innovative step towards enhancing visualization of PGs in real-time without requiring display monitors or administering any exogenous labels.
Supplementary Material
Video 1. Demonstration of fluorescence projection overlay with Overlay Tissue Imaging System (OTIS) is performed first with a grid sketched with near infrared (NIR) fluorescent ink, followed by testing with ex vivo specimens of parathyroid gland (adenoma), thyroid and lymph node tissues. The room lights are switched off during the workflow with OTIS. Note that when the target (grid or tissue specimen) is shifted or moved, the projection overlay also shifts accordingly – associated with a delay less than 2 seconds.
ACKNOWLEDGMENTS
We are grateful to the Vanderbilt University Medical Center hospital staff and surgical team involved for their assistance in data collection. We also thank Mr. Adnan Abbas (AiBiomed, Santa Barbara, California) for his input on optimizing system design. The authors are also thankful to Emmanuel Mannoh and Christine O’ Brien for their valuable guidance in preparing this manuscript.
Support: This work was supported by the National Science Foundation Graduate Research Fellowship Program under NSF-0909667 (to McWade) and the National Institutes of Health under Grant Nos. R41EB015291, R42CA192243 and 1R01CA212147-01A1 (to Mahadevan-Jansen).
Footnotes
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Supplementary Materials
Video 1. Demonstration of fluorescence projection overlay with Overlay Tissue Imaging System (OTIS) is performed first with a grid sketched with near infrared (NIR) fluorescent ink, followed by testing with ex vivo specimens of parathyroid gland (adenoma), thyroid and lymph node tissues. The room lights are switched off during the workflow with OTIS. Note that when the target (grid or tissue specimen) is shifted or moved, the projection overlay also shifts accordingly – associated with a delay less than 2 seconds.