bioresorbable evaporative microfluidics provides for reversible elimination of local peripheral nerve activity.
The experiments and simulations presented in this paper demonstrate that microfluidic evaporative cooling is an effective approach for reversibly and precisely cooling nervous tissue to suppress pain signals. This method's success suggests its potential for providing pain relief without the side effects associated with traditional pain medications.
Acute animal trials demonstrate the capability of evaporative microfluidic coolers to reversibly eliminate evoked nerve signals.
The cooling cuff successfully blocked nerve signals in rat sciatic nerves, and this effect was reversible once the nerve tissue returned to normal temperature. This suggests that the device could potentially function in humans too, based on this early evidence on an animal model.
Localization of the cooling effect to a predefined site without the need for insulating layers represents a key capability of the evaporative microfluidic cooling approach introduced here.
The device in this paper can selectively cool a precise area of nervous tissue without affecting the surrounding tissue, ensuring that only the targeted area receives the cooling effect. This targeted cooling allows for localized pain relief without impacting neighboring tissue, which contrasts with the broader effects of opioid medication.
The perfusion of blood through the targeted nerve presents an additional source of heat flux.
When attempting to cool nervous tissue, the effect of blood circulation should be considered, as it can counteract the cooling process by bringing heat to the cooled area.
systematically sweeping the PFP and N2 flow rates over the same range as in Fig. 3A reveal the effect of molar flow rates on resultant nerve temperature
The device in this study functions by circulating PFP through the microfluidic system, absorbing heat from its surroundings and evaporating. Dry N2, which is very cold, maintains PFP in its liquid phase, enhancing its heat absorption capacity before evaporation. Figure 3B illustrates that neither a high PFP nor N2 amount alone effectively cools the system, highlighting the necessity of both for successful nerve cooling. As depicted in figure 3C, an optimal PFP molar fraction of around 0.13 yields the most effective cooling outcome.
the effect of PFP flow rate on nerve-temperature cooling rate.
Increasing the PFP flow rate, as shown in Figure 3D, enhances the cooling rate of nerve tissue. This occurs because higher PFP flow pushes out warmed PFP more rapidly, allowing fresh, cooler PFP to absorb more heat in a shorter time. Adjusting PFP flow rate allows for controlling the tissue cooling rates.
For a nerve blood flow of 50 μl/min (Fig. 3H), the temperature of the nerve increases by 2.0°C (from 3.5° to 5.5°C).
In nerve tissue, heat is primarily transferred through direct contact, a process known as conduction. However, there's also convective heat transfer facilitated by surrounding biofluids and blood flow around the nerves. In the study, comparisons between environments where only conduction occurs (such as a hydrogel at 37°C) and those with convective effects (like water at 37°C) help illustrate these phenomena (Fig. 3G). Additionally, when the authors simulated the impact of blood flows through the targeted nerve, they found out that it contributes to a temperature increase of 2.0°C, highlighting the impact of perfusion on nerve temperature (Fig. 3H).
Nerve coolers embedded in a thermochromic tissue mimic in three different configurations serve as models for experimental study of temperature gradients in radial (Fig. 4A) and longitudinal (Fig. 4B) views along the nerve and across the surface of an uncurled, planar device (Fig. 4C).
Different orientations of the microfluidic cooling device enable precise cooling over specific regions, as the cooling effect is localized to the tissue in direct contact with the coils, rather than affecting the entire surrounding area. The cooling area within the layers of the hydrogel remains confined to the shape of the device on the surface.
Thermal three-dimensional finite element analysis confirms that the cooling effect is largely confined radially (Fig. 4G) and longitudinally (Fig. 4H) within the extent of the cooling cuff and above a flat cooler (Fig. 4I). The temperature of the vapor remains confined inside the microfluidic channel, as indicated by the cold region that extends radially down and to the right in the z = 0 mm plane for Fig. 4G.
The authors utilized finite element analysis (FEA) to demonstrate that the cooling effect of the device remains localized and does not extend beyond the applied area. As distance from the tissue surface increases, the cooling effect diminishes.
In devices constructed for multiday experiments, transcutaneous connections to a bioresorbable microfluidic evaporative cooler and temperature sensor mounted to the sciatic nerve (Fig. 5C) route subcutaneously along the spine to a headcap (Fig. 5D).
The cooling cuff is attached to the injured sciatic nerve and then routed along the spine to a headcap. This headcap is placed on the rat's head and allows for further monitoring and control of the device. Figures 5C-D illustrate how the device interfaces with the rat's sciatic nerve and the pathway of the connections to the headcap. The injured nervous tissue in the rat causes a pain response when touched, which is measured each time contact is made. By applying cooling with the device, this pain response should decrease and eventually be eliminated as the temperature decreases.
Previous in vivo studies of POC (21), Mg (30), SiO2 (31, 32), and cellulose acetate (33) provide additional strong evidence of biocompatibility and associated bioresorption processes.
Previous studies within living organisms have shown that other materials such as polyoctandiol citrate (POC), magnesium, silicon dioxide, and cellulose acetate may be good candidates for usage in bioresorbable devices and present biocompatible characteristics.
Cooling applied to peripheral nerves is a promising approach for blocking pain signals because it is nonaddictive, is rapidly reversible, can be applied locally, avoids any onset response, and allows for simultaneous electrical interrogation of the blocked nerve
A previous study showed that nerve cooling is (i) not addictive - unlike opioid medication - (ii) does not permanently harm or disable affected nervous tissue, (iii) can be applied to a small targeted area without affecting surrounding tissue, (iv) does not produce an adverse response immediately after being applied, and (v) allows for the nerves being cooled to be simultaneously monitored to measure electrical activity so that the cooling can be adjusted if needed.
Electromyography (EMG) of the tibialis anterior muscle indicates a 92% reduction in EMG magnitude and 64% increase in signal latency of neuromuscular activity during cooling from 31° to 5°C over a period of 8 min (Fig. 5A).
Electromyography is the measurement of muscle response or electrical activity in muscle tissue when stimulated by nerves. Here, they used electromyography while simultaneously cooling the nervous tissue responsible for activity in the tibialis anterior, a large muscle in the lower half of the leg. They perfomed it over various cooling temperatures from 31°C down to 5°C , and found that as the decreased the temperature, the electrical activity in the tibialis anterior decreased.
with effective moduli not substantially higher than those of peripheral nerves [rat sciatic nerve elastic modulus is 0.6 MPa
The rat sciatic nerve elastic modulus is 0.6 MPa, while the elastic modulus of the base material of the device, POC, is 2.8 MPa. This means that the device will deform and stretch even less than that of the present neural tissue in rats.
The elastic modulus of human neural tissue has been measured at 100 Pa to 10 kPa, meaning the device is vastly sufficient for human tissue as well.
Information about the human nerve tissue elastic modulus, as well as for other tissues, can be found at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519935/
A serpentine magnesium trace with a width and length of 25 μm and 72 mm, respectively, provides temperature feedback through the temperature coefficient of resistance of Mg
The resistance-based temperature sensor detects temperature changes by measuring variations in electrical resistance of the serpentine magnesium channel with changes in temperature.
The technology consists of a hybrid microfluidic and electronic system for cooling and simultaneously measuring the temperature of a peripheral nerve
The term microfluidic refers to the behavior and movement of fluids through micro-sized channels. In this device, perfluoropentane (PFP) flows through the microfluidic channels, and as it evaporates, it cools the surrounding system. The electronic system functions to measure the temperature of the surrounding nerves. The resistance-based temperature sensor detects temperature changes by measuring variations in electrical resistance with changes in temperature.
aberrant neural signals are well defined in select anatomical regions, (ii) nerves carrying aberrant neural signals are already isolated, and (iii) a need for opioid therapy exists after operation
The authors intend for this device to be used for pain management in cases where, after a patient undergoes a surgical operation, (i) the pain signals are in specific, contained parts of the body, (ii) the signals travel along specific nerves, ensuring that only the affected nerves are targeted while leaving others unaffected, and (iii) a non-addictive method of pain reduction is needed to avoid harmful long-term affects.
The microfluidic system includes transcutaneous colinear interconnects that deliver liquid coolant [perfluoropentane (PFP)] and dry N2 to a serpentine evaporation chamber
The system includes tubes that insert through the skin and connect to the device's cooling system along the same direction. The PFP functions as a coolant by absorbing the heat of the surrounding tissue, causing it to evaporate. The N2 is quite cold relative to PFP, so it keeps the PFP in a liquid state. The more N2, the more heat the system can absorb before the PFP evaporates, so changing the amount of N2 allows for control of the temperature change.
The mass flow rates of the PFP and N2 and the geometry of the evaporation chamber govern the magnitude and localization of the cooling effect. At low PFP molar flow ratios (XPFP = 0.1), the PFP fully evaporates after passing through three serpentines, with marginal liquid PFP buildup at the corners of the microchannels (Fig. 2C). At high molar flow rates (XPFP = 0.5), PFP proceeds through annular flow and passes along the sidewalls of the microchannels
The dry N2 is used to initially keep the PFP in a liquid state. For this experiment, the molar flow ratio is the ratio between the liquid nitrogen, N2, and the coolant gas, PFP. The authors conducted two experiments, the molar flow ratio at 0.1 and 0.5, respectively. They observed that at 0.1, PFP only made it through a fraction of the system before absorbing the heat of the surroundings caused it to completely evaporate, as there is not enough N2 to keep it in liquid form. At 0.5, they observed some PFP remaining in liquid form throughout the entire system, meaning the heat of the surroundings was not enough to overcome to cooling effect of the N2.
The simultaneous initiation of PFP and N2 flows into this structure prompts evaporation of PFP at the microfluidic junction between the PFP and N2 channels and along the serpentine chamber. PFP, which boils near room temperature (28° to 30°C), is bioinert and compatible with nonfluorinated elastomers.
The location and strength of the cooling effect by the device is controlled by how much of the liquid coolant, perfluoropentane (PFP), is supplied to the serpentine system, as well as the amount of liquid nitrogen, N2. The liquid nitrogen is very cold and keeps the PFP in a liquid state. The cooling is achieved when the PFP absorbs the heat of its surroundings, causing it to evaporate. This process is known as evaporative cooling.
The controlled input of electrical (4), pharmacological (5), optical (6), mechanical (7), or thermal (8, 9) stimuli to neural tissue can lead to local and reversible neural blocking
The nervous system senses pain by transmitting messages from the site of injury to the brain, which interprets the signals as pain and prompts appropriate responses to protect the body. Scientists have found that they can control these signals using different methods like electricity, drugs, light, physical force, or changes in temperature. By using these methods, they can temporarily stop or block the messages in a specific area of the body, and they can do it in a way that the blocking can be reversed when needed. This approach allows researchers to manage pain or control certain body functions without causing permanent damage to the nerves.
POC exhibits an elastic modulus of 2.8 MPa (21), controllable rates of degradation by means of surface erosion (22), and a demonstrated compatibility with nerves
Previous studies have shown that POC has a high elastic modulus, meaning that it can experience high stress and not become deformed. Furthermore, the rate at which it breaks down at the surface can be controlled, and it replicates the structure and mechanical properties of nervous tissue. The device developed by the authors in this paper needs all of these factors to function properly, making POC an ideal candidate.
shows devices wrapped around a silicone phantom nerve and submerged in phosphate-buffered saline (PBS) (pH 7.4) at 75°C, as an accelerated aging test. The results show that the materials largely dissolve within 20 days and that elimination of residues occurs after 50 days under these conditions
In this experiment, the authors wrapped the devices around a model silicone nerve and submerged them in a solution called phosphate-buffered saline (PBS) at a high temperature (75 C). PBS is a standard aqueous solution that mimics the chemical composition and pH of bodily fluids, such as blood and interstitial fluid. The high temperature simulates an accelerated aging process, allowing them to see how quickly the materials break down over time. The results revealed that the materials mostly dissolved within 20 days, and any remaining residues disappeared after 50 days under these conditions. This helps researchers understand how the devices will behave in the body over time and ensures they are safe and biocompatible.
soft, stretchable mechanics at the device level
The device was constructed with soft materials that can change shape and direction so that it can conform to the tissue without causing damage or blocking of important processes in the body. Furthermore, the functional components of the device were constructed so that they can continue to serve their purpose and remain intact while being stretched.
in a manner conceptually similar to that of other recently reported classes of bioresorbable sensors and therapeutic systems to monitor and accelerate wound healing or recovery processes
Earlier studies have utilized bioresorbability to address similar problems associated with the removal of implantable sensors. The sensors can be designed to begin dissolving immediately after implantation, but remain functional for some time until the main components disintegrate. The duration of the dissolution process can be controlled by the type and thickness of materials within the device.
Analgesic nerve cooling requires spatiotemporally precise control of temperature to maximize desired outcomes and to minimize the chance of cooling-induced tissue damage
In a prior investigation, researchers simultaneously cooled two sciatic nerves, which extend from the hip to just below the knee, using different methods: one continuously and the other intermittently, for the same duration. They observed a significant discrepancy in response between the two nerves; specifically that though some tissue damage was caused by both intermittent and continuous cooling, the intermittent cooling caused much more severe tissue damage. This suggests that the response of sensory nerves to cooling is highly dependent on the cooling procedure and duration of exposure.
Local cooling of peripheral nerves decreases conduction velocity and signal amplitude of neural activity
Peripheral nerves are the nerves outside of the brain and the spinal cord, extending through the rest of the body such as the arms and legs, and are responsible for sending and receiving information to and from the brain.
Cooling specific areas of the peripheral nervous system can cause a decrease in the speed of electrical impulses through the nerves and the strength of those impulses, making it more difficult for pain signals to reach the brain. Therefore, if the author can achieve contained, consistent cooling of certain nerves, they can prevent/reduce pain in patients.
metabolic, electrogenic, and ionic activity in neural tissue all exhibit a negative temperature dependence
This paper builds on research indicating that when the nerve environment cools down, the activity generating and transmitting nerve impulses decreases, thereby inhibiting the transmission of pain signals to the brain.
Miniaturized implantable devices that eliminate pain signals locally in peripheral nerves suggest a potential role for engineering-based treatments that avoid side effects associated with opioids
In past research, scientists have used peripheral nerve stimulation (PNS). This involves applying an electric field to certain areas of the spinal cord that send sensory signals to the brain. The electrical stimulation disrupts the nerves responsible for transmitting pain-related sensory information.
Blocking of transmission of compound action potentials in mammalian nerves typically occurs below 15°C (12), but this threshold can be temporarily increased to near room temperature by a brief heating period preceding the cooling period
Previous studies have shown that electrical impulses in the nervous system can be blocked by lowering the temperature to 15°C or less, however, if the area is briefly heated, then this cooling threshold can be increased to around 21°C, or room temperature.
implantation of a bioresorbable cooler around the nerve that innervates damaged tissue enables reversible elimination of neural activity and pain signals through the focused application of cooling power
The authors envision clinical applications for addressing acute pain after surgery, particularly in cases where specific nerves causing pain are known and opioid therapy is necessary. This implantable device provides targeted cooling to nerves surrounding damaged tissues, thereby offering an alternative to addictive and risky pain medications. The neural activity is temporarily blocked by cooling, and can be reversed after the treatment. The device is biodegradable, eliminating the necessity for surgical removal post-healing.
A bioresorbable elastomer, poly(octanediol citrate) (POC), forms the microfluidic system
The backbone of the microfluidic device is an elastic, biocompatible, rubber-like material on which the rest of the components of the device are attached.
constructed entirely with water-soluble constituent materials that controllably dissolve to biocompatible end products in the biofluids that are contained in subcutaneous tissues
The device in this paper was constructed exclusively with materials that dissolve at a predictable rate when exposed to the fluids contained at the deepest layer of the skin, and such that both the intact device and the products of the dissolving process are harmless and processable for the human body.