Effect of Needle Insertion Speed on Tissue Injury,Stress, and Backflow Distribution for Convection-Enhanced Delivery in the Rat Brain

Flow back along a needle track (backflow) can be a problem during direct infusion, e.g. convection-enhanced delivery (CED), of drugs into soft tissues such as brain. In this study, the effect of needle insertion speed on local tissue injury and backflow was evaluated in vivo in the rat brain. Needles were introduced at three insertion speeds (0.2, 2, and 10 mm/s) followed by CED of Evans blue albumin (EBA) tracer. Holes left in tissue slices were used to reconstruct penetration damage. These measurements were also input into a hyperelastic model to estimate radial stress at the needle-tissue interface (pre-stress) before infusion. Fast insertion speeds were found to produce more tissue bleeding and disruption; average hole area at 10 mm/s was 1.87-fold the area at 0.2 mm/s. Hole measurements also differed at two fixation time points after needle retraction, 10 and 25 min, indicating that pre-stresses are influenced by time-dependent tissue swelling. Calculated pre-stresses were compressive (0 to 485 Pa) and varied along the length of the needle with smaller average values within white matter (116 Pa) than gray matter (301 Pa) regions. Average pre-stress at 0.2 mm/s (351.7 Pa) was calculated to be 1.46-fold the value at 10 mm/s. For CED backflow experiments (0.5, 1, and 2 µL/min), measured EBA backflow increased as much as 2.46-fold between 10 and 0.2 mm/s insertion speeds. Thus, insertion rate-dependent damage and changes in pre-stress were found to directly contribute to the extent of backflow, with slower insertion resulting in less damage and improved targeting.     

Influence of needle insertion speed on backflow for convection-enhanced delivery

Fluid flow back along the outer surface of a needle (backflow) can be a significant problem during the direct infusion of drugs into brain tissues for procedures such as convection-enhanced delivery (CED). This study evaluates the effects of needle insertion speed (0.2 and 1.8 mm/s) as well as needle diameter and flow rate on the extent of backflow and local damage to surrounding tissues. Infusion experiments were conducted on a transparent tissue phantom, 0.6% (w/v) agarose hydrogel, to visualize backflow. Needle insertion experiments were also performed to evaluate local damage at the needle tip and to back out the prestress in the surrounding media for speed conditions where localized damage was not excessive. Prestress values were then used in an analytical model of backflow. At the higher insertion speed (1.8 mm/s), local insertion damage was found to be reduced and backflow was decreased. The compressive prestress at the needle-tissue interface was estimated to be approximately constant (0.812 kPa), and backflow distances were similar regardless of needle gauge (22, 26, and 32 gauge). The analytical model underestimated backflow distances at low infusion flow rates and overestimated backflow at higher flow rates. At the lower insertion speed (0.2 mm/s), significant backflow was measured. This corresponded to an observed accumulation of material at the needle tip which produced a gap between the needle and the surrounding media. Local tissue damage was also evaluated in excised rat brain tissues, and insertion tests show similar rate-dependent accumulation of tissue at the needle tip at the lower insertion speed. These results indicate that local tissue damage and backflow may be avoided by using an appropriate insertion speed.     

Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

Convection-enhanced delivery (CED) has been proposed as a treatment option for a wide range of neurological diseases. Neuroinfusion catheter CED allows for positive pressure bulk flow to deliver greater quantities of therapeutics to an intracranial target than traditional drug delivery methods. The clinical utility of real time MRI guided CED (rCED) lies in the ability to accurately target, monitor therapy, and identify complications. With training, rCED is efficient and complications may be minimized. The agarose gel model of the brain provides an accessible tool for CED testing, research, and training. Simulated brain rCED allows practice of the mock surgery while also providing visual feedback of the infusion. Analysis of infusion allows for calculation of the distribution fraction (Vd/Vi) allowing the trainee to verify the similarity of the model as compared to human brain tissue. This article describes our agarose gel brain phantom and outlines important metrics during a CED infusion and analysis protocols while addressing common pitfalls faced during CED infusion for the treatment of neurological disease.     

Subject-specific non-linear biomechanical model of needle insertion into brain

The previous models for predicting the forces acting on a needle during insertion into very soft organs (such as, e.g. brain) relied on oversimplifying assumptions of linear elasticity and specific experimentally derived functions for determining needle-tissue interactions. In this contribution, we propose a more general approach in which the needle forces are determined directly from the equations of continuum mechanics using fully non-linear finite element procedures that account for large deformations (geometric non-linearity) and non-linear stress-strain relationship (material non-linearity) of soft tissues. We applied these procedures to model needle insertion into a swine brain using the constitutive properties determined from the experiments on tissue samples obtained from the same brain (i.e. the subject-specific constitutive properties were used). We focused on the insertion phase preceding puncture of the brain meninges and obtained a very accurate prediction of the needle force. This demonstrates the utility of non-linear finite element procedures in patient-specific modelling of needle insertion into soft organs such as, e.g. brain.     

Designing and testing of backflow-free catheters

Convection-enhanced delivery (CED) is a drug delivery technique used to target specific regions of the central nervous system (CNS) for the treatment of neurodegenerative diseases and cancer while bypassing the blood-brain barrier (BBB). The application of CED is limited by low volumetric flow rate infusions in order to prevent the possibility of backflow. Consequently, a small convective flow produces poor drug distribution inside the treatment region, which can render CED treatment ineffective. Novel catheter designs and CED protocols are needed in order to improve the drug distribution inside the treatment region and prevent backflow. In order to develop novel backflow-free catheter designs, the impact of the micro-fluid injection into deformable porous media was investigated experimentally as well as numerically. Fluid injection into the porous media has a considerable effect on local transport properties such as porosity and hydraulic conductivity because of the local media deformation. These phenomena not only alter the bulk flow velocity distribution of the micro-fluid flow due to the changing porosity, but significantly modify the flow direction, and even the volumetric flow distribution, due to induced local hydraulic conductivity anisotropy. These findings help us to design backflow-free catheters with safe volumetric flow rates up to 10 μl/min. A first catheter design reduces porous media deformation in order to improve catheter performance and control an agent volumetric distribution. A second design prevents the backflow by reducing the porosity and hydraulic conductivity along a catheter's shaft. A third synergistic catheter design is a combination of two previous designs. Novel channel-inducing and dual-action catheters, as well as a synergistic catheter, were successfully tested without the occurrence of backflow and are recommended for future animal experiments.     

On the microstructurally driven heterogeneous response of brain white matter to drug infusion pressure

Delivering therapeutic agents into the brain via convection-enhanced delivery (CED), a mechanically controlled infusion method, provides an efficient approach to bypass the blood–brain barrier and deliver drugs directly to the targeted focus in the brain. Mathematical methods based on Darcy’s law have been widely adopted to predict drug distribution in the brain to improve the accuracy and reduce the side effects of this technique. However, most of the current studies assume that the hydraulic permeability and porosity of brain tissue are homogeneous and constant during the infusion process, which is less accurate due to the deformability of the axonal structures and the extracellular matrix in brain white matter. To solve this problem, a multiscale model was established in this study, which takes into account the pressure-driven deformation of brain microstructure to quantify the change of local permeability and porosity. The simulation results were corroborated using experiments measuring hydraulic permeability in ovine brain samples. Results show that both hydraulic pressure and drug concentration in the brain would be significantly underestimated by classical Darcy’s law, thus highlighting the great importance of the present multiscale model in providing a better understanding of how drugs transport inside the brain and how brain tissue responds to the infusion pressure. This new method can assist the development of both new drugs for brain diseases and preoperative evaluation techniques for CED surgery, thus helping to improve the efficiency and precision of treatments for brain diseases.

     

A nonlinear biphasic model of flow-controlled infusion in brain: Fluid transport and tissue deformation analyses

A biphasic nonlinear mathematical model is proposed for the concomitant fluid transport and tissue deformation that occurs during constant flow rate infusions into brain tissue. The model takes into account material and geometrical nonlinearities, a hydraulic conductivity dependent on strain, and nonlinear boundary conditions at the infusion cavity. The biphasic equations were implemented in a custom written code assuming spherical symmetry and using an updated Lagrangian finite element algorithm. Results of the model showed that both, geometric and material nonlinearities play an important role in the physics of infusions, yielding important differences from infinitesimal analyses. Geometrical nonlinearities were mainly due to the significant enlargement of the infusion cavity, while variations of the parameters that describe the degree of nonlinearity of the stress–strain curve yielded significant differences in all distributions. For example, a parameter set showing stiffening under tension yielded maximum values of radial displacement and porosity not localized at the infusion cavity. On the other hand, a parameter set showing softening under tension yielded a slight decrease in the fluid velocity for a three-fold increase in the flow rate, which can be explained by the substantial increase of the infusion cavity, not considered in linear analyses. This study strongly suggests that significant enlargement of the infusion cavity is a real phenomenon during infusions that may produce collateral damage to brain tissue. Our results indicate that more experimental tests have to be undertaken in order to determine material nonlinearities of brain tissue over a range of strains. With better understanding of these nonlinear effects, clinicians may be able to develop protocols that can minimize the damage to surrounding tissue.     

Experimental study of needle–tissue interaction forces: Effect of needle geometries,insertion methods and tissue characteristics

A thorough understanding of needle–tissue interaction mechanics is necessary to optimize needle design, achieve robotically needle steering, and establish surgical simulation system. It is obvious that the interaction is influenced by numerous variable parameters, which are divided into three categories: needle geometries, insertion methods, and tissue characteristics. A series of experiments are performed to explore the effect of influence factors (material samples n=5 for each factor) on the insertion force. Data were collected from different biological tissues and a special tissue-equivalent phantom with similar mechanical properties, using a 1-DOF mechanical testing system instrumented with a 6-DOF force/torque (F/T) sensor. The experimental results indicate that three basic phases (deformation, insertion, and extraction phase) are existent during needle penetration. Needle diameter (0.7–3.2 mm), needle tip (blunt, diamond, conical, and beveled) and bevel angle (10–85°) are turned out to have a great influence on insertion force, so do the insertion velocity (0.5–10 mm/s), drive mode (robot-assisted and hand-held), and the insertion process (interrupted and continuous). Different tissues such as skin, muscle, fat, liver capsule and vessel are proved to generate various force cures, which can contribute to the judgement of the needle position and provide efficient insertion strategy.     

Quantitative Examination of Tissue Concentration Profiles Associated with Microdialysis

Spatial solute concentration profiles resulting from in vivo microdialysis were measured in rat caudate-putamen by quantitative autoradiography. Radiolabeled sucrose was included in the dialysate, and the tissue concentration profile measured after infusions of 14 min and 61.5 min in an acute preparation. In addition, the changes in sucrose extraction fraction over time were followed in vivo and in a simple in vitro system consisting of 0.5% agarose. These experimental results were then compared with mathematical simulations of microdialysis in vitro and in vivo. Simulations of in vitro microdialysis agreed well with experimental results. In vivo, the autoradiograms of the tissue concentration profiles showed clear evidence of substantial differences between 14 and 61.5 min, even though the change in extraction fraction was relatively small over that period. Comparison with simulated results showed that the model substantially underpredicted the observed extraction fraction and overall amount of sucrose in the tissue. A sensitivity analysis of the various model parameters suggested a tissue extracellular volume fraction of approximately 40% following probe implantation. We conclude that the injury from probe insertion initially causes disruption of the blood-brain barrier in the vicinity of the probe, and this disruption leads to an influx of water and plasma constituents, causing a vasogenic edema.     

A computational approach to investigate optimal cutting speed configurations in rotational needle biopsy cutting soft tissue

The rotational cutting method has been used in needle biopsy technologies to sample tough tissues, such as calcifications in the breast. The rotational motion of the needle introduces shear forces to the cutting surface such that the cutting force in the axial direction is reduced. As a result, tissue samples with large volume and better quality can be obtained. In order to comprehensively understand the effect of the needle rotation to the axial cutting force under a wide range of the needle insertion speed, this paper demonstrates a computational approach that incorporates the surface-based cohesive behavior to simulate a rotating needle cutting soft tissue. The computational model is validated by comparing with a cutting test dataset reported in the literature. The validated model is then used to generate response surfaces of the axial cutting force and torque in a large parameter space of needle rotation and insertion speeds. The results provide guidelines for selecting optimal speed configurations under different design situations.     

Detailed finite element modelling of deep needle insertions into a soft tissue phantom using a cohesive approach

Detailed finite element modelling of needle insertions into soft tissue phantoms encounters difficulties of large deformations, high friction, contact loading and material failure. This paper demonstrates the use of cohesive elements in high-resolution finite element models to overcome some of the issues associated with these factors. Experiments are presented enabling extraction of the strain energy release rate during crack formation. Using data from these experiments, cohesive elements are calibrated and then implemented in models for validation of the needle insertion process. Successful modelling enables direct comparison of finite element and experimental force–displacement plots and energy distributions. Regions of crack creation, relaxation, cutting and full penetration are identified. By closing the loop between experiments and detailed finite element modelling, a methodology is established which will enable design modifications of a soft tissue probe that steers through complex mechanical interactions with the surrounding material.     

Frictional insertion kinetics of bone biopsy needles.

Patients undergoing a percutaneous bone biopsy often complain of pain during needle insertion, despite local anesthesia. Bone biopsy needles are typically inserted with combined axial and twisting motions. These motions could cause pain through frictional heating or direct mechanical irritation. The hypothesis of this study is that the insertion energy of bone biopsy needles can be reduced by modifying the insertion kinetics or by adding a friction-lowering coating to the needles. Jamshidi bone biopsy needles were driven into a bone analog model by an MTS materials testing machine operating under axial and rotational displacement control. The load/torque recordings showed that, to significantly decrease insertion energy and peak resistance to needle insertion, axial velocity and angular frequency had to be decreased to one quarter of the baseline, typical-usage parameters. However the increased insertion time may not be acceptable clinically. The majority of the insertion energy was associated with the needle axial thrust rather than with needle twisting. Overcoming friction against the side of the needle consumed much more of the insertion energy than did the process of cutting per se. None of five needle coatings tested succeeded in appreciably lowering the insertion energy, and none achieved a substantial decrease in peak resisting force.     

Anatomical differences determine distribution of adenovirus after convection-enhanced delivery to the rat brain

Background

Convection-enhanced delivery (CED) of adenoviruses offers the potential of widespread virus distribution in the brain. In CED, the volume of distribution (Vd) should be related to the volume of infusion (Vi) and not to dose, but when using adenoviruses contrasting results have been reported. As the characteristics of the infused tissue can affect convective delivery, this study was performed to determine the effects of the gray and white matter on CED of adenoviruses and similar sized super paramagnetic iron oxide nanoparticles (SPIO).

Methodology/Principal Findings

We convected AdGFP, an adenovirus vector expressing Green Fluorescent Protein, a virus sized SPIO or trypan blue in the gray and white matter of the striatum and external capsule of Wistar rats and towards orthotopic infiltrative brain tumors. The resulting Vds were compared to Vi and transgene expression to SPIO distribution. Results show that in the striatum Vd is not determined by the Vi but by the infused virus dose, suggesting diffusion, active transport or receptor saturation rather than convection. Distribution of virus and SPIO in the white matter is partly volume dependent, which is probably caused by preferential fluid pathways from the external capsule to the surrounding gray matter, as demonstrated by co-infusing trypan blue. Distant tumors were reached using the white matter tracts but tumor penetration was limited.

Conclusions/Significance

CED of adenoviruses in the rat brain and towards infiltrative tumors is feasible when regional anatomical differences are taken into account while SPIO infusion could be considered to validate proper catheter positioning and predict adenoviral distribution.     

A nonlinear biphasic model of flow-controlled infusions in brain: Mass transport analyses

A biphasic nonlinear mathematical model is proposed for the mass transport that occurs during constant flow-rate infusions into brain tissue. The model takes into account geometric and material nonlinearities and a hydraulic conductivity dependent upon strain. The biphasic and convective–diffusive transport equations were implemented in a custom-written code assuming spherical symmetry and using an updated Lagrangian finite element algorithm. Results of the model indicate that the inclusion of these nonlinearities produced modest changes in the interstitial concentration but important variations in drug penetration and bulk concentration. Increased penetration of the drug but smaller bulk concentrations were obtained at smaller strains caused by combination of parameters such as increased Young’s modulus and initial hydraulic conductivity. This indicates that simulations of constant flow-rate infusions under the assumption of infinitesimal deformations or rigidity of the tissue may yield lower bulk concentrations near the infusion cavity and over-predictions of the penetration of the infused agent. The analyses also showed that decrease in the infusion flow rate of a fixed amount of drug results in increased penetration of the infused agent. From the clinical point-of-view, this may promote a safer infusion that delivers the therapeutic range over the desired volume while avoiding damage to the tissue by minimizing deformation and strain.     

Prestress as an optimal biomechanical parameter for needle penetration

Drug delivery requires precise intradermal and subcutaneous injections of formulations to clinically relevant penetration depths. However, penetration depth is confounded by skin deflection, which occurs prior to and during penetration as the skin surface deforms axially with the needle, and which varies profoundly due to differing intrinsic mechanical (e.g. viscoelastic) tissue properties, disease state, aging, and ethnicity. Herein, an ex vivo model was utilized to study factors that affect skin deflection and the efficacy of injection, including prestress applied at the tissue surface, needle gauge, velocity, and actuation depth. The application of prestress minimized skin deflection during needle penetration and allowed for needle actuation to the targeted penetration depths with minimum variability. The force required to achieve target penetration depths was found to increase with prestress and decrease with needle gauge. Our findings emphasize the need for prestress applied to the skin surface to minimize variation in skin properties and administer formulations for intradermal and subcutaneous treatments with maximum precision.     

Comparison of porcine brain mechanical properties to potential tissue simulant materials in quasi-static and sinusoidal compression

In both finite element and physical surrogate models of head blast injury, accurate material properties of the brain and/or tissue simulants are necessary to ensure biofidelity in predicted response. Thus, there is a need for experimental comparisons between tissue and simulant materials under the same experimental conditions. This study compares the response of porcine brain tissue and a variety of brain tissue simulants in quasi-static and sinusoidal compression tests. Fresh porcine brain tissue was obtained from a local abattoir and tested within 4 h post mortem. Additionally, the effect of post mortem time was investigated by comparing samples stored at room temperature and stored frozen (−18 °C), at various time intervals. The brain tissue simulants tested were bovine gelatin (3%, 5%, and 10% concentration), agarose gelatin (e0.4%, 0.6%, 0.8% concentration), and Sylgard 527. The experiments were performed using a DMA apparatus (TA Instruments Q800). The quasi-static compression data were fit to Ogden hyperelastic functions so that parameters could be compared. It was found that bovine gelatin at 3% and 5% concentration demonstrated the closest response to brain tissue in quasi-static compression. Conversely, in sinusoidal compression, the agarose gel and Sylgard 527 were found to be in closer agreement with the tissue, than bovine gel. In terms of post mortem time and storage, there was no statistically significant difference detected in the response of tissue samples after 48 h, regardless of storage method. However, samples stored at room temperature after 48 h appeared to demonstrate a reduction in stiffness.     

Restricted clinical efficacy of cyclosporin A on rat transient middle cerebral artery occlusion

The immunosuppressant cyclosporin A (CsA) has been shown to have neuroprotective action. The inhibition of both calcineurin activation and mitochondrial permeability transition pore (mtPTP) opening are considered the primary neuroprotective mechanisms of CsA. Here we have evaluated the effect of CsA on significantly reducing infarct size induced by transient middle cerebral artery occlusion (MCAO) in rats, and examined variable therapeutic applications for brain infarction. Experimental rats were divided into 12 groups according to: CsA administration time (immediately after occlusion or immediately after reperfusion); dosage (between 10 and 50 mg/kg); route (i.v. or i.p.); and with or without needle insertion, which hypothetically disrupts the blood brain barrier (BBB). Neuroprotective effects of CsA were hardly noticeable when administered immediately after occlusion or by i.v. injection. By needle insertion, CsA administration significantly reduced infarct size, although vehicle treatment also reduced infarct size compared with nontreatment animals, i.e. no needle insertion. These results suggest that needle insertion allows endogenous neuroprotective substances to pass into the brain. Furthermore, single dosages over 30 mg/kg CsA were excessive and negated potential neuroprotective effects. However, two i.p. administrations of 20 mg/kg CsA immediately and 24 hrs after reperfusion significantly ameliorated the infarct size compared to the vehicle-treated group. We conclude that CsA exhibits significant neuroprotective activity, although its therapeutic application for stroke may be limited by very strict and precise management requirements.     

Static and dynamic imaging of alveoli using optical coherence tomography needle probes

Imaging of alveoli in situ has for the most part been infeasible due to the high resolution required to discern individual alveoli and limited access to alveoli beneath the lung surface. In this study, we present a novel technique to image alveoli using optical coherence tomography (OCT). We propose the use of OCT needle probes, where the distal imaging probe has been miniaturized and encased within a hypodermic needle (as small as 30-gauge, outer diameter 310 μm), allowing insertion deep within the lung tissue with minimal tissue distortion. Such probes enable imaging at a resolution of ～12 μm within a three-dimensional cylindrical field of view with diameter ～1.5 mm centered on the needle tip. The imaging technique is demonstrated on excised lungs from three different species: adult rats, fetal sheep, and adult pigs. OCT needle probes were used to image alveoli, small bronchioles, and blood vessels, and results were matched to histological sections. We also present the first dynamic OCT images acquired with an OCT needle probe, allowing tracking of individual alveoli during simulated cyclical lung inflation and deflation.     

Passive marker tracking via phase-only cross correlation (POCC) for MR-guided needle interventions: Initial in vivo experience

PurposeIn this work, a passive tracking sequence employing a phase-only cross correlation (POCC) algorithm was studied with a focus on the in vivo applicability of the technique. Therefore, MR-guided needle interventions were performed in a phantom and two animal experiments.MethodsThe targeting accuracy was quantified in an agarose phantom with 15 fiducials. For each fiducial, the distance between needle trajectory and target point was measured. In a first animal experiment at 3 T, the prostate of a pig was punctured under POCC guidance. Second, POCC-based tracking was performed during a laser-induced thermal therapy procedure in peripheral porcine muscle tissue at 1.5 T.ResultsIn the phantom experiment, the 15 fiducials were penetrated with a mean accuracy of 1.5 ± 0.9 mm (mean duration for one puncture about 2 min). In the first animal experiment, the center of the pig's right prostatic lobe was accurately punctured within 15 min. In the second, targeting and insertion of the needle could be performed within 5 min and a thermal lesion was successfully created.ConclusionOur initial experience with the POCC-based tracking sequence indicates that this technique has the potential as an accurate and versatile tool for in vivo MR-guided needle interventions.