This study showed that the investigated OI/X-ray system in conjunction with ICG-injection is a suitable technique to depict granulation tissue after spine surgery. Unique to this imaging system is its ability to acquire and fuse OI and X-ray images and thereby, facilitate an anatomical orientation with respect to the associated level of the lumbar spine. In addition, this investigation revealed certain advantages of using a high dose of 10 mg/kg of ICG, as opposed to a lower dose of 1 mg/kg. The dose of 10 mg/kg of ICG provided a stronger and prolonged enhancement of the granulation tissue thus allowing for longer observation times and improved detection of disease. Of note, the FDA approved ICG dose for clinical applications is 1 mg/kg. Although our data shows that this dose is sufficient to depict granulation tissue, future studies should evaluate if higher doses are also advantageous in the clinical setting.
The sensitivity of the OI/X-ray approach provides advantages over the current standard, MR imaging. T2-weighted MR images and gadolinium-DTPA-enhanced T1-weighted MR images reveal detailed information about the exact location and vascularization of granulation tissue as well as related displacement and thickening of nerve roots [30
], but MR scans have a limited sensitivity. Peng et al. argued that standard clinical MR scans with 3–4 mm thick slices may not be able to detect small and poorly vascularized areas of granulation tissue [31
]. Our study demonstrates that granulation tissue with an extent of 2–3 mm can be clearly depicted with OI. Furthermore, OI is easier to apply, faster (acquisition time is in the order of seconds) and is markedly less expensive compared to MR. In addition, new handheld OI scanners may allow investigators to perform studies at the bedside. Therefore, the high sensitivity of our OI technique provides an essential advantage for the detection of postoperative granulation tissue.
To the best of our knowledge, OI has not been used to image postoperative granulation tissue. However, other fluorescent dyes have been successfully employed for the detection of other chronic inflammations, such as arthritis [32
]. ICG is superior to other fluorescent contrast agents for several reasons. ICG is FDA-approved for use in patients. It has been used to measure tissue blood volumes, cardiac output and hepatic function [34
]. In addition, ICG has been applied for the detection of tumors [35
], for angiography in ophthalmology [38
] and for imaging of experimental arthritis [39
]. ICG provides an excellent penetration depth of light in tissue because it displays strong absorption (~805 nm) and an intense emission spectra (~830 nm), which occur at wavelengths for which blood and other tissues are relatively transparent [40
]. Finally, because of ICG's high affinity for blood proteins, it displays enhancement kinetics of a blood pool agent [41
When applied in low concentrations, the majority of the agent stays in the intravascular compartment and, thus, leads to an early and short enhancement of the target tissue. Conversely, when applied in high concentrations, the biliary elimination of the agent is saturated, resulting in a prolonged circulation time and leaking across the hyperpermeable endothelium of the microvessels in the granulation tissue with every perfusion. This results in a slow accumulation of the agent in the interstitium of the granulation tissue, reflected by a slowly increasing and prolonged enhancement on OI. This prolonged enhancement of granulation tissue with the high ICG dose may be advantageous for potential future applications of handheld OI scanners, which are currently under development.
Our data showed that the integrated OI/X-ray system is particularly valuable for musculoskeletal and orthopedic applications. Potential drawbacks of the fusion technique could be misregistrations of the imaging data due to movement. Since our animals were anesthetized, we did not encounter any problems of this nature. However, potential clinical applications would have to provide an additional setup (e.g. holding devices) to avoid patient movement and consecutive misregistrations of imaging data. One limitation of our study is that we were not able to separate perivertebral and perineural granulation tissue because of the small anatomy of the rodent spine. Future clinical applications have to show, if the larger anatomy in patients will allow a separation of these two locations of granulation tissue.
With the number of clinical spine surgeries increasing every year, the management and treatment of postoperative granulation tissue is an increasing problem [2
]. Treating this granulation tissue is of crucial importance in order to prevent complications in postoperative patients [42
]. New anti-inflammatory therapeutics are currently being developed that aim to decrease the development and growth of granulation tissue and, thereby, decrease associated postoperative complications. The new OI-/X-ray technique, described in this study, will be applied as a non-invasive and cost-effective tool to directly and non-invasively monitor the efficacy of new anti-inflammatory drugs for the suppression of postoperative granulation tissue. In addition, the described OI technique is in principle ready to be applied in patients and could be used at the bedside once handheld OI scanners become available.