Abstract
Intrathecal delivery of opiates directly into the cerebrospinal fluid (CSF) is the oldest technique for the delivery of anesthetics to the central nervous system (CNS). Despite the long empirical experience with spinal anesthetics, the relationships between CSF dynamics and biodistribution of intrathecally delivered drugs are complex and the mechanisms that lead to this complex distribution are poorly understood. First-principle models of fluid mechanics have been created to elucidate complex flow patterns in subject-specific computations. It has also been shown that complex CSF flow patterns are responsible for the vigorous mixing effects that govern the biodistribution of intrathecally delivered drugs. This chapter aims to link CSF flow patterns to expected drug dispersion. However, predicting the biodistribution of drugs is not an easy task.
Due to the difficulty of access to the CNS, computational analysis capable of interpreting spatial and temporally distributed imaging data plays a vital role in elucidating pharmacokinetics and pharmacodynamics of intrathecal drug delivery. We review progress in our lab as well as the open literature to give a snapshot of this very active field. The chapter aims to understand better the relationship between infusion parameters and achievable drug distribution. In the near future we expect that the integration of imaging data with first-principle computational models such as those described here will enable us to design more effective drug administration strategies so that specific cells and tissue in any point of the CNS can be more effectively targeted than is the case with existing methods. We close by pointing out research directions that will pave the way for these imminent developments.
Keywords
CSF flow, Intracranial dynamics, Intrathecal drug delivery
Outline
Introduction 829
Understanding Dynamic CSF Flow 830
Introduction to Pulsatile CSF Dynamics and CSF–Parenchyma–Vasculature Coupling 830
Respiratory Influence on CSF Flow 832
Geometry-Induced Flow Phenomena (Nerve Roots and Trabeculae) 832
Cilia-Induced CSF Flow in the Cerebral Ventricles 832
Acquisition of CNS Anatomy 833
CSF Flow Measurements 833
CSF Production and Reabsorption 833
Classical Hypothesis 833
The New Hypothesis of CSF Production and Reabsorption in the Brain 834
Osmotic Gradient-Driven Flow 834
The Role of Perivascular Spaces on Tracer Transport 834
Intrathecal Drug Transport and Delivery 834
Intrathecal Administration Therapy 835
Cerebrospinal Fluid Pulsation 835
Infusion Type: Bolus Versus Drug Pump 836
Impact of Drug Chemistry on Pharmacokinetics 836
In Vitro and Mathematical Models for Predicting IT Drug Dispersion 837
In Vitro Models of the CNS 837
In Silico Models of IT Delivery 838
Nanoparticles for Magnetically Guided Therapies 839
Modeling Limitations of the Perivascular Space 839
Design of Optimal Therapies for Intrathecal Administration 840
Future Directions and Open Questions 840
Open Issues 841
References 842
Introduction
This chapter reviews the relationships between cerebrospinal fluid (CSF) dynamics and drug biodistribution following intrathecal (IT) administration. We attempt to provide the reader with a very thorough state-of-the-art review of the assessment of CSF dynamics that occurs with natural pulsations inside the spinal and cranial subarachnoid spaces (SAS). CSF dynamics are important because the fluid flow patterns significantly determine the biodistribution of IT delivery. Specifically we show that the oscillatory flow and complex mixing that occurs in the central nervous system (CNS) are responsible for the fast dispersion observed in anesthesia of intrathecally delivered morphine.
This chapter is organized into an introduction of CSF dynamics and cerebrovascular coupling, which is a major driving force of CSF pulsations, and the potential influence of respiration. We also discuss the measurement of CSF flow patterns. We review CSF production and reabsorption, its origins, and its physiochemical relationships with osmolarity and water transfer at the microscopic level. The section on IT drug transport and delivery addresses critical factors that impact IT drug transport with relevance to IT drug administration, anesthesia pain management, and the delivery of gene vectors. The factors discussed here are important for future models or tools to model CSF flow as well as for clinicians to predict the biodistribution of intrathecally delivered drugs. The section on in vitro and mathematical models for predicting IT drug dispersion introduces recent advances in mathematical models for rational design of IT drug administration. Specifically, it illustrates in vitro models as well as computational approaches to predict drug distribution after IT administration. Novel approaches to steering nanoparticles after IT administration are shown in a subsection on magnetic guidance of nanoparticles, which can be useful for magnetically guided chemotherapy. Finally, we close with innovative perspectives on treatment guidelines. These guidelines are understood as a compass for future directions for more innovative applications that go beyond the current clinical practice.
Understanding Dynamic CSF Flow
Introduction to Pulsatile CSF Dynamics and CSF–Parenchyma–Vasculature Coupling
Current research into CSF velocities, CNS motion, and even respiratory influences are advancing the study of CSF dynamics, but critical questions remain. What is the exact nature of the force coupling between the pulsatile blood circulation with CSF displacements ( )? The exact source location and type of force coupling between the expanding and contracting vasculature, brain movement, and induced CSF dynamics are uncertain. This could elucidate key insights for transport phenomena of agents administered to the CSF. An additional question is whether perivascular solute transport is facilitated by naturally occurring convection under physiological conditions, which would require insights into the coupling between CSF motion and vascular pulsations. Also, the observed rapid penetration of tracer molecules through perivascular spaces observed in infusion experiments may have a strong pulsatile origin. The answer is of significant interest for treatment therapies of the CNS, where it could be exploited for achieving more rapid drug dispersion. A diagram of the main anatomical structures in the CNS is provided in Fig. 67.1 .
In our present view, we see CSF motion in the fluid-filled spaces mainly induced by vascular expansion. Imaging studies have confirmed that the cardiac cycle imposes its pulsatile pattern on to the CSF ( ). CSF also flows from the cranial to the spinal SAS in systole, with flow reversal from the spinal subarachnoid spaces into the cranium in diastole. Pulsatile CSF oscillations are believed to be driven by systolic vascular dilatation followed by diastolic contraction.
During the normal cardiac cycle, 550–950 mL of blood are pumped into the head per minute through the internal carotid artery and two vertebral arteries which discharge into the Circle of Willis before distribution to major cerebral territories ( ). The systolic pressure rise is believed to inflate blood vessels, thus augmenting the cerebral blood volume during systole. Due to the rigid cranial vault, the vascular expansion of the main cerebral arteries forces CSF displacement. This hypothesis is known as the Monro–Kellie doctrine. Magnetic resonance imaging (MRI) evidence suggests that the total cerebral blood volume inflates and deflates in each cardiac cycle by approximately 1–2 mL, the same volumetric amount, as there is CSF exchange between the cranial and spinal SAS ( ).
In addition to pulsations of the main arteries running along the cortical surface, smaller penetrating arterioles or the capillary bed, both of which are embedded inside the cortical tissue, may distend. Volumetric dilatation of the microcirculatory structures would need to be transmitted to the surrounding parenchyma. Brain tissue dilation would in turn have to displace interstitial fluid (ISF) through the extracellular space (ECS) into the ventricular system or produce brain motion ( ).
An MRI technique deployed by permitted the quantification of ventricular wall motion. This source of motion could originate from vascular volume dilatation transmitted from the cortical surface through brain tissue, whose compression causes ventricular contraction. Alternatively, ventricular wall motion could arise from inside the ventricles by systolic expansion of the choroidal arteries, such that ventricular walls pulsate against the periventricular ependymal layer. Ventricular dilation due to choroid expansion was hypothesized in a theoretical model and measured with cine phase-contrast MRI (PC MRI) ( ), which is a technique triggered by the heartbeat and captures data over a full cardiac cycle.
In addition to arterial expansion, compression of the venous system under high pressure has been hypothesized, which would reduce the venous blood lumen by cross-sectional area deformation or even collapse of sections of the venous tree ( ). speculated that the venous system is compressible, especially in patients with high intracranial pressure (ICP). Diminished venous lumen induces feedback that lowers blood flow, owing to the hike in resistance ( ). The possible collapse of vertebral blood flow when ICP exceeds a threshold (typically 30 mmHg) and reduced blood flow occurring in benign cerebral hypertension supports the notion of a compressible or collapsible venous bed ( ).
Moreover, the caudal decrease in CSF flow amplitude along the spinal canal ( ) supports the hypothesis of compliant tissue boundaries confining the CSF-filled spaces. Observed CNS compliance could result from periodic volume displacement within spinal or cranial veins, or the expansion of the elastic boundaries of the spinal SAS.
Respiratory Influence on CSF Flow
studied the effect of cardiac pulsations and respiration in spinal CSF movement in healthy volunteers. They concluded that cardiac pulsations are the main driver of CSF flow, but respiration plays a dominant role in the thoracolumbar region ( ). A respiratory influence on the CSF oscillations in the aqueduct has been observed in many studies ( ). The study by Dreha-Kulaczewski used volunteers who practiced forced breathing and breath holding, and found high CSF flow during inspiration phases. , used two-dimensional (2D) PC MRI to apply a correlation mapping technique to CSF flow in the cranial space of seven volunteers. The underlying finding was that the spatial distribution was different between the two components, suggesting different originating locations and mechanisms for driving CSF; one such example was the high correlation of cardiac pulsation in the prepontine region and high correlation for respiration along the venous sinus ( ).
employed real-time PC MRI with in vivo subjects to study the relative impact of respiration and cardiac pulsations on CSF flow dynamics using an MR technique to detect signal frequencies not aligned with the cardiac output. In human volunteers they found deep controlled breathing forced CSF cephalad at the foramen magnum during inhalation and caudad during exhalation. CSF flow during natural breathing was more influenced by cardiac pulsations.
Growing interest in the respiratory component as a driving motor for CSF flow has elucidated that both respiration and cardiac pulsations influence CSF motion. The respiration influence has been identified as distinct from the cardiac phase, and the respiratory influence has been shown to be strongest in the thoracolumbar region. Forced respiration was shown to override cardiac pulsations, but the forced exercise does not represent the natural relationship between cardiac pulsations and baseline breathing. The question of relative strength of influence on CSF flow for cardiac versus respiratory driving forces remains undetermined. Further studies are needed to disentangle the relative effects between breathing and cardiac cycle, as well as spinal and cranial compliance. Patient-specific factors such as spinal and cranial compliance, CSF volumes, and heart rate and respiration frequency variation may prohibit a generalized scheme for attributing CSF dynamics to individual driving components. The open question regarding the driving motor of CSF flow lends weight to the argument to consider each subject individually.
Geometry-Induced Flow Phenomena (Nerve Roots and Trabeculae)
Nerve roots connecting the CNS with the peripheral nerves extend between the spinal pia mater and the outer dura mater crossing the spinal CSF-filled space. The protruding nerve roots constitute geometric obstructions to unhindered CSF flow, inducing vigorous steering in the spinal CSF with eddies and recirculation zones. Microanatomical features causing complex flows also include ligaments, spinal–arachnoid midline septa, trabeculae, and meningeal layers, which were carefully characterized by .
Solute dispersion in an annular spine segment was studied by . Microanatomical features increased solute dispersion up to 10-fold when compared to a simulation on a model without nerve roots and trabeculae. Biodistribution of an IT-administered drug was studied by Hsu et al. in an idealized axisymmetric spinal and cranial SAS ( ). The authors report that pulse amplitude and frequency were key factors affecting the speed and spread of drug distribution. Tangen et al. predicted drug distribution in a subject-specific three-dimensional (3D) model of the entire CNS, confirming that anatomical features in the spine enhance mixing and the rapid spread of the drug ( ). The computational analyses revealed that nerve roots and trabeculae create vortices, which break the laminar flow profiles in the pulsating CSF of the spine and thus increase the rate of drug spread. In effect, convective drug transport is rapid despite a low Reynolds number and slow drug diffusivity. Our characterization of the geometry-induced flow regimes, also known as chaotic advection ( ), with associated micromixing patterns has significant implications for local anesthesia and chronic pain management.
Cilia-Induced CSF Flow in the Cerebral Ventricles
Recently ependymal cilia lining the cerebral ventricles were shown to influence near-wall CSF flow in mice ( ). A study on the third ventricle of the mouse brain elucidated a transport network driven by organized cilia motion. Additionally, these cilia were able to induce complex flow patterns and change flow direction. The overall contribution of these near-wall flow effects is an ongoing area of research, but they could have a potential role in substance distribution within the ventricles ( ).
Acquisition of CNS Anatomy
MRI is a standard technique to measure CSF flow velocities and acquire anatomical structures. CSF exhibits dark signals in T1-weighted images, which are commonly used in image segmentation for reconstructing models of cerebral structures, including the CSF space, gray matter, and white matter. Multiple groups have proposed automatic or semiautomatic image-processing algorithms for segmentation of the CSF space ( ). T2-weighted images capture CSF as a bright signal and are widely used for clinical diagnosis of CSF-related diseases, including hydrocephalus and aqueduct stenosis ( ). CSF flow measurements require a different imaging protocol, briefly described next.
CSF Flow Measurements
PC MRI
Quantitative CSF flow is measured by PC MRI ( ), which uses a velocity-encoding gradient to generate signal contrast between flowing and stationary hydrogen atoms. Stationary hydrogen atoms generate a zero signal, while moving hydrogen atoms, such as those in flowing blood or CSF, exhibit a positional change-producing signal. Cardiac gating, which synchronizes MRI acquisition with the cardiac cycle, can enhance the sensitivity of pulsatile CSF measurements ( ). Flow quantification is often hindered by the low flow magnitude (typical velocity-encoding thresholds are 5–8 cm/s— ) and reversal in flow direction that occurs in spinal CSF motion. Moreover, CSF spaces do not conform to uniform shapes, which complicates the determination of perpendicular planes needed in volumetric flow measurements. These difficulties diminish the precision of CSF flow measurements ( ). Furthermore, the large anatomical domain makes PC MRI a time-consuming way to measure CSF flow throughout the neuronal axis.
Four-Dimensional MRI
Due to the limitations of PC MRI measurements, researchers have used volumetric acquisition protocols with cardiac-gated PC MRI, also known as four-dimensional MRI (4D MRI) ( ). Two approaches are being pursued: fast 3D MRI to acquire volumetric images in real time, and fast 2D MRI to acquire images from all respiratory phases continuously and retrospectively sort these images. The typical temporal resolution of real-time 4D MRI is greater than 1 s and the voxel size is 4 mm ( ). Overall, the image quality of real-time 4D MRI is low, given the lack of spatial resolution. The second approach requires a respiratory surrogate to monitor patient motion during image acquisition ( ). Compared to real-time 4D MRI, the image quality of retrospectively sorted 4D MRI is improved, motion artifacts are largely reduced, given the fast image acquisition, and the voxel size is smaller with increased spatial resolution. Disadvantages of this technique include a longer acquisition time as every other image is acquired purely for sorting purposes.
Current Developments
Current developments for CSF measurement using MRI involve imaging sequence design for faster acquisition and finer resolution. Contrast-enhanced MRI using gadolinium as a biomarker is also used for better highlighting of transport phenomena ( ). Other imaging techniques can provide additional information to monitor CSF dynamics, such as tracking radio-labeled tracer distributions using positron emission tomography (PET). PET-computed tomography can provide pharmacokinetic data for intrathecally infused agents ( ).
CSF Production and Reabsorption
Classical Hypothesis
The classical view of CSF production states that secretion occurs at the choroid plexus epithelium through an active process, which is plausible due to specialized epithelial cells capable of fluid secretion. It is vascularized by fenestrated capillaries, in contrast to tight capillary junctions found in most parts of the brain. Complete removal of the choroid plexus in primate models reduces CSF production by 33%–40%, but the composition is not significantly different ( ). Moreover, CSF accumulates in the ventricles during induced obstructive hydrocephalus, even in animals without choroid plexii. The classical view of CSF production cannot explain why choroid plexectomy does not mend the symptoms of hydrocephalus. In a study by , cauterization of the choroid plexus failed to reduce ventricular size significantly in any patient, and 65% of patients required a CSF shunt to achieve long-term control of symptoms. These observations suggest that the choroid plexus is not the only site of CSF production.
CSF is believed to be reabsorbed into the venous system through the arachnoid villi, protrusions of the arachnoid membrane into the superior sagittal sinus (SSS) located at the top of the head, or alternatively though nerve paths into the extracranial lymphatic system. Fluid reabsorption in the SSS occurs via endothelial cell-lined channels within arachnoid granulations (AGs) lining the subarachnoid space ( ). Further evidence for the communication between CSF and venous blood comes from size exclusion studies showing that smaller particles pass through AGs while larger particles are retained ( ). These results suggest that AGs facilitate fluid and solute exchange. There is evidence of additional fluid-exchange mechanisms in the brain, specifically in animal experiments which suggest that lymphatic drainage is significant in rodents ( ) and dogs ( ). However, the extent of lymphatic drainage in humans is still debated ( ).
The New Hypothesis of CSF Production and Reabsorption in the Brain
Recently an additional hypothesis for fluid exchange in the brain has been proposed which suggests hydrostatic and osmotic pressure gradients induce water filtration and reabsorption across cerebral capillaries. Osmotic pressure gradients have been shown to be a significant driving force for water ( ) and solute exchange ( ) between the blood, parenchyma, and CSF. Cisternal perfusion experiments suggest that the blood–CSF barrier at the choroid plexus is not the only interface, but there is constant fluid and solute exchange between blood, CSF, and ISF throughout the brain parenchyma. These observations form the foundation of the microcirculation hypothesis ( ), according to which water is first filtered across the blood–brain barrier (BBB) but then reabsorbed into more distal capillaries or venules, driven by hydrostatic and osmotic pressure gradients.
Osmotic Gradient-Driven Flow
The role of osmolarity exercising Starling forces needs to be quantified to determine the amount and directionality of bulk water exchange across the BBB ( ). Water exchange from astrocytic endfeet into the ECS sparked a growing interest in transmembrane proteins known as aquaporin channels ( ). Despite these developments, a high degree of uncertainty about the amount, direction, and physiochemical driving forces of ISF exchange remains. The role of physiological mechanisms driving CSF production, reabsorption, and hydrostatic pressures inside the brain is still poorly understood.
The Role of Perivascular Spaces on Tracer Transport
Distinct and apart from extracellular movement of ISF, perivascular tracer transport experiments suggest a separate fluid conduit which exists between the leptomeninges and the arterial endothelium along arteries ( ). The morphology of the perivascular space (PVS) is different in arterioles and venules according to the arrangement of endothelial, pial, and glial cells ( ). At the level of penetrating arterioles, the PVS forms a gap between the vessel endothelium and the pial sheath. As arterioles branch into capillaries, the pial sheath becomes increasingly fenestrated and is absent at the capillary level ( ). Cortical venules lack a pial sheath but exhibit a layer at the level of the SAS ( ). However, the transport mechanisms of the PVS are a subject of continued research and debate ( ).
Experimental studies on the PVS use radioactive tracers injected into the SAS, which rapidly disperse into the interstitial space by penetrating arterioles ( ). The speed by which radioactive tracers penetrate into the brain parenchyma via the PVS suggests that these solutes are transported by convection, perhaps by chaotic advection. It has been speculated that systolic arterial expansion also drives pulsatile transport phenomena in the PVS ( ), but actual volumetric flow rates of ISF flux in the PVS have so far not been quantified. Experimental evidence from tracer ( ), microscopy ( ), and neuroimaging ( ) studies further suggests the existence of a preferential pathway for water and solutes around an annular region surrounding cerebral blood vessels.
Intrathecal Drug Transport and Delivery
The CNS presents unique difficulties for targeted drug delivery. The BBB limits the effectiveness of systemic drug administration, restricting 98% of small therapeutic molecules ( ). Directly introducing compounds into the CSF of the CNS via IT injection bypasses this barrier, thereby creating a route for pain management. Thus this mode of drug delivery requires a smaller dosage for analgesic efficacy when compared to systemic administration. In addition, confining the active agent to the CNS reduces systemic side-effects. However, the fate of active agents in the CSF following injection is poorly understood, limiting the ability to improve these techniques ( ). Quantitative tools could have a role in adjusting IT injection scenarios to improve pharmacodynamics and provide potential guidelines for desired delivery.
The ability to bypass the BBB creates a unique opportunity for access of therapeutic drugs to the CNS. We show in this chapter that by understanding the CSF flow patterns it is possible to target specific locations in the CNS. We first illustrate critical factors that affect drug dispersion of agents administered to the CNS, then discuss the impact of infusion type, the influence of infusion volume, and the role of pharmacokinetic and reaction kinetic properties on the expected biodistribution.
Intrathecal Administration Therapy
IT drug delivery is a method to bypass the BBB, and has commonly been used for the management of spasticity ( ) and chronic pain ( ). The enormous potential of IT delivery for effective administration of enzyme replacement gene therapies has been explored in primate and human trials ( ). To improve upon these therapies, it is imperative to understand critical factors affecting biodistribution, such as injection impulse and drug-binding kinetics ( ). A tool to provide more information to clinicians could have a role in tailoring IT injection scenarios to improve patient treatments and provide potential guidelines for desired delivery. What is needed for predicating and rationally designing IT therapies is acquiring the CSF flow field and the ability to reconstruct subject-specific anatomy. Fig. 67.2 shows an example of how MRI acquisition of anatomical and CSF flow profiles is incorporated into a model to predict CSF flow patterns and drug biodistribution. Fig. 67.3 shows an example of how computational methods are able to elucidate the influence of injection volume and rate coupled with natural CSF pulsations, which are unable to be observed in vivo.
Cerebrospinal Fluid Pulsation
The biodistribution after IT injections was observed in systematic in vitro experiments using dye injections ( ). The observed dye spread was subject to two phases, the first dominated by injection impulse and the second governed by convective dispersion due to CSF pulsations. The pulsation amplitude and frequency have been identified as key factors for drug dispersion after IT delivery ( ). During weaker pulsation the drug spread is slow and confined to the site of infusion. Under faster pulsation rates the rate of biodistribution is increased, leading to a larger volume of distribution in the spinal canal.
Infusion Type: Bolus Versus Drug Pump
Infusion rate and volume largely define the initial stages of drug distribution in the SAS. IT drugs can be administered by either bolus injection or continuous infusion, such as through a drug pump ( ). Low-rate injections exhibit a similar effect of reduced rostral spread. However, a high-volume injection of drug such as morphine may rapidly progress, even reaching the brain, due to injection-induced flow jets. This scenario may be concerning, in that a large volume of drug going to the brain and brainstem could lead to respiratory complications. Future studies can use modeling efforts to examine high-risk infusion scenarios and provide information to clinicians on infusion parameters, which could reduce complications associated with IT injection of anesthetic agents. In high-volume injection the initial volume of distribution could be extended by a factor of 10 over low-volume infusion. The evidence from suggests that a drug will appear in the intracranial CSF if the administration is over 10% of the total estimated CSF volume.
In drug injection pumps for chronic use, the largest effect on biodistribution stems from natural CSF pulsatility and the drug’s half-life. Simulation results on multiple subjects with a modeled drug pump infusion rate of 0.005 mL/min demonstrated that drug distribution remains close to the injection site. If the drug is very readily taken up in the tissue it will not travel far when administered slowly from a drug pump. Thus use of lipophilic drugs is preferential for lower regions in long-term treatment. Local delivery can be maximized by low-uptake drugs with slow-release mechanisms. Caution must be exercised with low infusion settings, since high local concentrations can cause spinal granuloma ( ).
A less commonly implemented technique utilizes a combination of bolus injections to reach different levels of the spinal SAS. Takiguchi et al. injected epidural saline following IT injection of dibucaine for analgesia, and noted an increased cranial transport of a dye ( ). In another theoretical study we have further demonstrated fluid coinfusion for the purpose of advancing a drug faster to reach more rostral targets ( ). The rationale for including a bolus with flush was to reach a more cranial target site. Multiple bolus infusions with drug-free components could be of interest for gene therapy studies, which require cervical or cortical target regions. Multibolus and high-volume injections may also in the future become relevant for enzyme replacement or gene therapies targeting the brain parenchyma ( ). However, there is a limit on how much fluid can be inserted into the CSF. In our experience with small animals ( ), injection volumes of 10%–15% of the total CSF volume are an upper limit.
Impact of Drug Chemistry on Pharmacokinetics
Drug choice and administration protocol greatly affect how a drug distributes in the spinal canal. Baclofen, anesthetics, and opioids are regularly used in IT administration, but the physiochemical properties of each drug gives rise to different pharmacokinetics in the SAS and CNS tissue. The governing property for the tissue permeability of drugs is lipophilicity in small molecular compounds ( ). IT-administered drugs of high and low lipophilicity exhibit low tissue permeability, while drugs of moderate lipophilicity readily cross the CSF–tissue boundary ( ). Fentanyl and alfentanil, drugs with high and moderate lipophilicity respectively, have high transfer rates into the epidural space ( ). Alfentanil absorbs into the spinal cord and then rapidly diffuses into blood plasma; its residency time in the cord is not long enough for a sustained therapeutic delivery. Fentanyl readily transfers into the epidural space before crossing into blood plasma, with very little drug residing in the cord. Morphine remains the gold standard for pain management because it exhibits the widest SAS distribution, with a moderate permeability into the spinal cord and little loss into the epidural space.
We show in the next section how the concepts discussed here, such as infusion volume, rate, and species reaction kinetics, can be integrated with state-of-the-art modeling of IT drug delivery options. We then review the ability to study CSF flow patterns and species biodistribution experimentally with in vitro experiments and in silico models. Additionally, we explore emerging topics such as magnetically guided nanoparticle drug delivery in the CSF.
In Vitro and Mathematical Models for Predicting IT Drug Dispersion
Modeling of IT drug delivery is important, due to the inaccessibility of the CNS and also the several experimental limitations of in vivo work. Despite recent advances in MRI, which allows us to quantify CSF flow, or PET scanning, which enables tracking of drug distribution, there are certain shortcomings. Specifically, MRI usually employs averaging, so the significant micromixing pattern (chaotic advection) that occurs in the CSF flow cannot be resolved. This means MRI is limited to average velocities and average volumetric flow rates, but cannot resolve the extremely important micromixing patterns that are actually driving drug dispersion ( ). A similar limitation is observed in PET, in which the advancement of drug fronts can be observed, but for the targeting of the spine it is not clear if the labeled tracers are in the fluid space or the tissue compartment, which complicates the analysis of pharmacokinetics and pharmacodynamics of drugs.
Given these limitations, a special role falls to two techniques that are becoming more prevalent. The first involves realistic in vitro models using 3D printed replicas of the subject-specific spinal geometry, which are able to reproduce fluid mechanical CSF distribution patterns that are close to reality. The second powerful tool available to the clinician and scientist is mathematical models of IT drug delivery. These can enable physicians to predict the effect of their infusion parameters choices prior to administration in a patient. This tool can provide them with a detailed 3D map as well as in a real-time map that illustrates where the drugs are expected to distribute.
We show progress specifically from our lab, which has been pioneering the use of computational tools that enable physicians to design optimal therapies for their patients in silico before applying treatments to their actual patients. Case studies of therapy design using virtual-reality-assisted computational methods ( ) demonstrate infusion scenarios ranging from morphine for pain management to possibilities to deliver advanced treatment options to the CNS, such as gene therapies for enzyme replacement. While such computational methods are not needed for the routine application of anesthetics, for which a vast body of experience is available clinically, optimal and safe design of infusion parameters in silico may be highly desirable for novel drugs that have not been tested and for which clinical data is unavailable. Here computations may provide invaluable information for designing experiments in animals, better interpreting animal data for the scale-up of therapies, or optimally choosing infusion parameters for the needs of a specific patient.
We also introduce emerging concepts of magnetic targeting, which allows IT-administered drugs to be controlled and steered to desired locations with the help of magnetic fields. The potential of nanoparticles for drug delivery has been widely recognized ( ). Specifically, one novel opportunity titled magnetic drug targeting steers superparamagnetic nanoparticles to desired locations for applications such as spinal tumors or brain tumors. Magnetically guided chemotherapy for spinal cord tumors, particularly intramedullary tumors, is quite appealing, since the standard of therapy is limited to modalities such as surgery, radiation, and chemotherapy, which experience limited success.
In Vitro Models of the CNS
Computational microcirculation patterns are difficult to observe in humans or animal models because of limited image resolution and slow acquisition rates of in vivo MRI flow measurements. For example, averaging over multiple cardiac cycles is necessary because current MRI methodologies have relatively slow acquisition rates. Specifically, geometry-induced microcirculatory flow patterns or high-speed jets that occur during drug injection cannot be observed by MRI; thus high-speed experimental techniques to study CSF flow and drug dispersion in realistic surrogate models of the cranium and spine are imperative for future research into IT therapies ( ). Spinal CSF flow patterns due to microanatomical aspects have been studied in an in vitro spine model with deformable boundaries ( ). Experimental tracer distribution studies on the spine model demonstrated that microanatomy-induced vortices substantially enhance drug transport. Fig. 67.4 gives an example of how cutting-edge additive manufacturing techniques can be employed to generate a precise 3D-printed replica of the entire spinal column, including CSF-filled spaces, using high-resolution medical images of a specific subject ( ). These models can use materials such as elastic polymers to create a model which deforms realistically under natural CSF pulsations, thereby mimicking physiological reality. Furthermore, the 3D-printed model in Fig. 67.4E is transparent to allow for tracer tracking studies of IT drug distribution.
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