1.

Introduction

Identification of the cavernous nerves (CNs) during prostate cancer surgery is critical in preserving a man’s sexual function following surgery. Because of the close proximity of the nerves to the prostate surface, they are at risk of injury during dissection and removal of a cancerous prostate gland. The exact location and path of these microscopic nerves also varies significantly among patients. These observations may explain the wide variability in sexual potency rates (9 to 86%) following surgery.¹ Development of improved methods for intraoperative identification of the CNs may prove valuable for preserving the nerves and improving postoperative sexual function and patient quality of life.

Numerous experimental nerve mapping devices and imaging modalities have been tested recently as potential intraoperative tools for identification of the CNs during prostate cancer surgery; however, they all have significant limitations.^2,3 Some of these technologies, including electrical nerve mapping devices, have been tested in the clinic.⁴ However, electrical nerve mapping has proven inconsistent and unreliable in identifying the CNs and evaluating nerve function. Lack of specificity, high false positive responses, and the influence of multiple conflicting factors in recording an electrical response during surgery have been cited.⁵6.^–7 Furthermore, electrical nerve stimulation (ENS) suffers from several inherent limitations, including need for physical contact between electrode and tissue, limited spatial precision due to electrical current spreading in tissue, and electrical artifacts that may interfere with measurement.

Optical nerve stimulation (ONS) using infrared (IR) laser energy provides several advantages, including noncontact stimulation, improved spatial selectivity, and elimination of stimulation artifacts.⁸ Our laboratory is developing ONS⁹10.11.12.13.^–14 as a potential alternative to ENS using a standard in vivo rat prostate model.¹⁵

The ONS mechanism has recently been identified primarily as a photothermal process.^16,17 The nerve temperature during ONS is therefore the most critical parameter. The temperature range necessary for successful ONS is relatively narrow, from $\sim 42$ to 47°C. Lower temperatures do not result in nerve activation¹⁸ and higher temperatures result in undesirable thermal damage to the nerve.¹⁹ Significant temperature fluctuations currently occur during both pulsed and continuous-wave (CW) delivery of laser radiation during ONS. Rapid, safe, and reproducible ONS may therefore require application of a constant temperature during laser irradiation.

Closed-loop feedback systems utilizing an IR sensor for real-time control of tissue surface temperatures during laser therapy have previously been reported for laser tissue welding and soldering applications.²⁰21.22.^–23 The therapeutic window for successful laser tissue welding is relatively large (e.g., 50 to 100°C), allowing for significant error in temperature control without adverse thermal effects in the tissue. However, for the specific application of ONS, the therapeutic window for successfully activating the nerves is much narrower, thus representing a greater challenge.

The ultimate goal of our laboratory is to develop a safe and effective ONS system as an intraoperative diagnostic tool for identification and preservation of the CNs during surgical excision and removal of a cancerous prostate gland. In this preliminary study, we describe the construction, characterization, and initial testing of a closed-loop, automated, temperature-controlled ONS (TC-ONS) system in an established in vivo rat prostate model for maintaining a precise, preset nerve temperature ($\pm 1°\mathrm{C}$). This TC-ONS system may prevent nerve damage due to an uncontrolled escalation in nerve temperature that may otherwise occur during conventional pulsed and CW methods of ONS.

2.

Materials and Methods

2.4.

Temperature Feedback System

The TC-ONS system consisted of three main components: an all-SMF laser system with mechanical shutter, a custom laparoscopic laser probe, and a radiometer with a temperature feedback control system. The radiometer system was composed of a thermopile digital sensor module (Heimann HID L14 FL5.5 T50, Boston Electronics, Bookline, Massachusetts), a zinc selenide (ZnSe) plano-convex IR lens (LA7733-F, Thorlabs) with transmission in the spectral range of 600 nm to 16 μm, and a microprocessor (QSK62P, Renesas Technology, Santa Clara, California). A photograph of the real-time, temperature-controlled all-SMF ONS system is shown in Fig. 1 along with the experimental setup. The thermopile sensor used in this system had an absorbing area of $0.37{\mathrm{mm}}^2$; it was sensitive to the 5.5 to 13.5 μm spectral range and generated a pulse-width modulation signal that was proportional to the temperature. The response time of the detector was 5 ms with a refresh rate between 100 and 250 ms. The mid-IR radiation emitted from the heated nerve surface was collected and transmitted to the IR sensor, generating a signal by use of a focusing lens with a 40 mm working distance. The output signal from the IR sensor was processed using a microprocessor for data acquisition and control. The actual control of laser power over the nerve surface was accomplished by providing rapid on/off switching with an optical shutter, based on an external transistor–transistor logic signal provided from a laptop PC.

Fig. 1

(a) Photograph of temperature-controlled optical nerve stimulation system (TC-ONS). (b) Experimental setup for ONS of the rat prostate cavernous nerves.

2.5.

Computer Ray-Tracing Simulations

Computer simulations using basic and complex ray-tracing methods (FRED Optical Engineering Software version 10.41.0, Photon Engineering, Tucson, Arizona) were also performed to provide a better understanding of propagation of the IR radiation through the two-lens optical system. These simulation studies were helpful not only to determine the optimal position of the IR lenses but also to optimize the aperture size and optimal position, which was critical to having a correct focusing power onto the CN and spatial resolution for accurate temperature measurements. Figure 2 shows the computer simulations in two-dimensional format. Light beams from a point source (black) and collimated light beams (red) were used to symbolize the IR radiation emitted from the heated spot on the nerve surface and the IR radiation emitted from surrounding tissue, respectively. These beams were collected with the use of an IR lens (20 mm focal length) as an objective lens (Lens1). Using a 1-mm-diameter aperture, undesired radiation (collimated light) was successfully minimized. The filtered radiation was transmitted through the IR sensor by a focusing IR lens (Lens2) with a focal length of 5.5 mm.

Fig. 2

Computer simulation of two-lens optical system with an aperture for filtering purposes. Lens1 had a focal length of 20 mm and was spaced 40 mm from the source and the detector. Lens2 was contained within the packaging of thermopile sensor from the manufacturer.

3.

Results

The CN temperature and ICP response were measured as a function of laser irradiation time for CW mode at different power levels and for TC-ONS mode at different temperature set points. The overall objectives were (1) to produce a rapid ramp-up in nerve temperature to the desired set-point temperature and (2) to maintain this constant set-point temperature during the stimulation period.

Figure 3 shows plots of the CN temperature and ICP response as a function of laser power and time. A 15 s baseline temperature is shown ($t=0$ to 15 s), followed by 15 s stimulation ($t=15$ to 30 s), and then 30 s postirradiation nerve cooling phase ($t=30$ to 60 s). Three different ONS modes were plotted under these conditions: CW at a power of 62 mW, TC-ONS at 62 mW with a set point of $\sim 42°\mathrm{C}$, and CW at a lower power of 52 mW which resulted in the same final nerve temperature of $\sim 42°\mathrm{C}$ at the end of stimulation ($t=30\mathrm{s}$). This graph shows two major differences. First, by comparing CW stimulation (62 mW) without temperature control to CW stimulation (62 mW) with TC-ONS, it was observed that the temperature set point prevented a continuous rise in the nerve temperature and maintained the nerve temperature at $42\pm 1°\mathrm{C}$. Second, by comparing CW stimulation (62 mW) with TC-ONS and CW stimulation (52 mW) without temperature control, we observed that at $t=30\mathrm{s}$, both graphs showed a final temperature of $\sim 42°\mathrm{C}$. However, the TC-ONS provided a faster ramp-up to the final temperature, thus translating into a faster ICP response time (7 versus 12 s) as well. A rapid ICP response is critical if ONS is to be adopted as an intraoperative diagnostic technique in the clinic.

Fig. 3

Cavernous nerve temperature and ICP response as a function of time for a 15 s stimulation ($t=15$ to 30 s). Use of higher laser power (62 mW) in CW mode allowed the nerve to reach the necessary temperature range for nerve activation more rapidly, generating a faster ICP response time ($\sim 7\mathrm{s}$). However, high power CW operation produces continuously escalating temperatures, eventually resulting in thermal damage to the nerve. Conservative use of lower laser power (52 mW) resulted in an unnecessary delay in reaching the nerve activation temperatures necessary for a robust ICP response ($\sim 12\mathrm{s}$). The TC-ONS system allowed both use of higher laser power for a shorter and faster initial ramp-up time in temperature and ICP, while also maintaining the nerve at a constant, preset temperature for safety.

In Fig. 4, the nerve temperature and ICP are plotted as a function of laser power or set-point temperature and time, with a 15 s baseline and a 30 s stimulation time. Five different conditions are shown: CW stimulation (94 mW) without temperature control and stimulation with TC-ONS at set points of 42, 44, 46, and 48°C corresponding to laser powers of 79, 84, 94, and 94 mW, respectively. Similar ICP response times were observed for the similar nerve temperature ramp-up times. However, ICP responses with higher peak values due to the higher final nerve temperatures were also observed.

Fig. 4

Cavernous nerve temperature and ICP response as a function of time for a 30 s stimulation ($t=15$ to 45 s). CW stimulation (94 mW) was compared to TC-ONS with set-point temperatures of 42, 44, 46, and 48°C corresponding to laser powers of 79, 84, 94, and 94 mW, respectively. Similar ICP response times were observed for similar nerve temperature ramp-up times. However, higher set-point temperatures resulted in more robust ICP responses.

4.

Discussion

Preservation of the CNs during prostate cancer surgery has proven challenging due to the close proximity of the CNs to the prostate surface, their microscopic nature, and their variation in location and path among patients. New technologies capable of identifying the CNs would aid in their preservation and result in improved postoperative sexual function and patient quality-of-life. Temperature-controlled laser systems have been previously tested for laser tissue welding and soldering applications. This preliminary study demonstrates the feasibility of TC-ONS of the rat CNs.

In summary, application of higher CW laser power allows the nerve to reach the necessary temperature range for nerve activation more rapidly, thus potentially generating both a faster and stronger ICP response. Both a fast and robust ICP response is necessary if ONS is to be suitable as an intraoperative diagnostic technique in the clinic. However, use of higher CW laser power also results in a continuously escalating nerve temperature and, if left uncontrolled, can eventually produce temperatures that cause thermal damage to the nerve ($T\ge 48°\mathrm{C}$). On the contrary, conservative use of lower CW laser power will result in an unnecessary delay in the temperature rise in the nerve, a potentially slower ICP response time, and a weaker ICP signal, making the method impractical in the clinic. The prototype TC-ONS system tested in these preliminary studies allowed use of higher laser power for a shorter and faster initial ramp-up time in nerve temperature and ICP response, respectively, while also maintaining the nerve at a constant ($\pm 1°\mathrm{C}$), preset temperature for safety.

Furthermore, it should be noted that, in general, there is a relatively large matrix of laser parameters that need to be studied during CW and, especially, pulsed modes for ONS (Table 1), making optimization of those techniques unnecessarily complex. Another advantage of TC-ONS is that this technique effectively decreases the number of relevant parameters to a single parameter, the nerve activation temperature, which is critical for successful, reliable, and safe ONS. Since ONS is believed to operate based on a photothermal response in the nerve, it is logical that the primary focus of parameter optimization should be the nerve temperature.

Table 1

Laser parameters that need to be optimized for pulsed, continuous-wave (CW), and temperature-controlled (TC) nerve stimulation for a given laser wavelength.

One limitation of our preliminary TC-ONS design was the difficulty in precisely calibrating the temperature sensor. While the sensor was chosen due to its small size (for future integration into a probe) and low cost, the sensor had limited temperature resolution and stability. The sensor had a resolution of ~1°C compared to ~0.1°C for the thermal camera. Subtle environmental temperature variances around the sensor casing were also believed to cause a drift of up to a few degrees Celsius in the calibrated temperature reading of the sensor. Improved thermal isolation of the sensor will therefore be necessary to maintain stability before this system is ready for clinical testing.

Another limitation is the background radiation seen by the IR sensor. IR radiation emitted by the two-lens optical system (Fig. 2), including IR lenses and an aperture, and the walls of the handle must be accounted for during calibration studies of the radiometer. Use of a single broadband IR sensor also results in temperature measurements which are sensitive to the tissue emissivity ($\epsilon$). Because of high water content in soft tissue, it is assumed that $\epsilon \sim 1$. However, the nerve structure is also expected to introduce a nonuniform emissivity distribution. A higher spatial resolution can also be achieved by decreasing the aperture diameter in the two-lens optical system if needed. Finally, future work will also include integration of the temperature sensor and the SMF probe into a single, compact, handheld instrument.

5.

Conclusions

This preliminary study has demonstrated that a prototype TC-ONS system is capable of maintaining a constant and relatively precise nerve temperature, critical for safe and reliable stimulation of the prostate CNs. Further development of this system is warranted to provide improved sensor temperature resolution and stability, given the relatively narrow therapeutic window of temperatures for successful ONS.