Patent Application
20110071425
{The field of the invention is medical and neuroscience instrumentation for research, clinical diagnostics and therapy, particularly for size-selective molecular sampling and delivery of fluid-borne agents to and from interstitial fluid in the brain, or in cerebro-spinal fluid in the spinal column.}
A micro-probe capable of sampling and delivery of relatively large particles, such as protein molecules, cells and microorganisms with minimal fluid transfer or trauma to selected sites in the brain may be of great utility in neuroscience research, clinical diagnostics or treatment of epilepsy and other neurological conditions.
Relevant prior art includes the use of the push-pull cannula, which comprises two adjacent, open-end cannulae with one cannula carrying the “pushed fluid” downward, whereas the other one carrying the “pulled fluid” upward, creating an open molecule-exchange zone at the tip of the two cannulas. This method was widely used in the sixties and seventies; it then became clear that the technique has the serious problems of frequent clogging of the cannulae by tissue or by clotting of fluids and damage to tissue by fluid build-up around the open-end cannula-tips. Alternative prior art teaches the use of microdialysis probes. The innovation of the microdialysis probe was the replacement of the open-end cannula-tips of the push-pull method with a microdialysis probe or fiber containing a semi-permeable membrane. This eliminated the blockage of perfusion inside the cannulae and prevented unwanted tissue damage. Yet, the very innovation that gave birth to this technique, the use of the microdialysis membrane, led to another problem: the inability to collect and deliver large particles, including such critical biological substances as proteins; these particles and molecules are very large and cannot pass through the membrane. It has become clear that new approaches are needed, and this micro-probe is a response to this need.
The Laser-Perforated Intra-Parenchymal Micro-Probe (“LAPP”) comprises a fluid manifold body having inlet and outlet ports connected respectively to the interior volume of a nested, coaxial dual-lumen cannula or microtube, in which the inlet port feeds the inner cannula, and the outlet port drains the annular volume (external to the inner cannula and internal to the outer cannula), such that the tip of the outer cannula is sealed, and the only fluid access between fluid inside the microtube assembly and the external biological tissue in which the microtube is inserted is provided by an array of laser-perforated apertures having a uniform size selected to enable extraction of molecules or fluid-borne material, but excluding any material of size greater than that of the apertures. Conversely, the aperture size also allows delivery of size-limited fluid-borne material. Connection of the inlet and outlet ports to independently programmable fluid pumps allows operation of the micro-probe according to a variety of protocols, enabling sampling (extraction) or delivery of fluid-borne material with net zero or non-zero fluid volume extracted or delivered, along with positive sampling or delivery of the fluid-borne molecules or material.
The Laser-Perforated Intra-Parenchymal Micro-Probe provides a minimally invasive means for sampling and delivery of picoliter/microliter fluid volumes, with selective size control on transfer of suspended material or molecules. These micro-probes, herein referred to as the “device”, provide alternatives to and significant improvements on current microdialysis membrane probe technology; these improvements relate to (1) greater dynamic selectivity range for transferred molecule (or particle) size, (2) pressure-augmented diffusion-driven molecular (or particulate) transfer capability, (3) durability under fluid pressure and mechanical force, (4) service lifetime and (5) tolerance of cleaning procedures for repeated use. This invention was developed with the aid of NIH grants #1R43NS049714-01, #9R44 MH080693-02 and #5 R44 MH080693-03.
The device comprises multiple sections of thin-wall tubing, retained in intersecting bores in a multi-port manifold body. The manifold and tubing provide access for fluid extraction or delivery. The manifold body may be fabricated from stainless steel, titanium, ceramic, glass, acetyl, or some other biocompatible material. The tubing must also be a biocompatible material, not necessarily the same as that of the manifold body. Appropriate material selection allows fabrication of probes which are compatible with MRI and other diagnostic procedures. The laser-perforated design has the ability to size-selectively exclude materials from extracted or delivered fluid; it may also minimize tissue damage at the sampling or delivery site by distributing the fluid volume interface over multiple small orifices covering a much larger area than a plain needle tip.
In the simplest steady-state operation mode, the delivery pump 5 and sampling pump 9 are driven at identical, non-zero volume-controlled flow rates. Fluid is forced through the delivery port 6, down the coaxial inlet tube 4 and exits into the interior of the main microtube 1 at the flow reversal region 12. It is then drawn through the annular flow region 13 until it flows out through the oblique outlet tube 7 and exits through the sampling port 8 into the sampling pump 9. Fluid in internal contact with the laser-drilled aperture array 3 in the selective transfer area 14 may transfer molecules or suspended material to or from the fluid environment outside of the main microtube 1, provided that said molecules or suspended material are smaller than the size of the laser-drilled apertures. The transfer of molecules or suspended material across the selective transfer area 14 may be driven in several modes by diffusion and/or local differential fluid pressure. These transfer modes are dependent on the operating protocol for the delivery pump 5 and sampling pump 9.
Diffusion transfer rate proportional to difference in concentration is expected, resulting in exponential time-decay to asymptotic concentration balance.
Mode 2: Constant Non-Zero Identical Delivery and Sample Flow, with Equal Fluid Pressure Inside and Outside the Aperture Array.
Diffusion transfer is expected to be proportional to local difference in concentration, with temporal asymptotic approach to dynamic equilibrium of concentration as a function of linear position in aperture array with respect to local flow axis.
Diffusion transfer is expected to be proportional to local difference in concentration as in mode 1 and mode 2, modified by a monotonic function of instantaneous flow rate.
Mode 4: Asymmetric Pulsed Delivery and Sample Flow, with Identical Mean Delivery and Mean Sample Flow Rates, but with Phase Differences Between Delivery and Sample Flow Pulses.
In this case, diffusion transfer is augmented by temporary non-zero volume exchange and mixing. This is expected to result in greater molecular transfer than mode 3, but will require a more complex representation or model. This mode involves more risk of tissue damage if the temporary non-zero net volume exchange is allowed to be too large; it also offers the potential advantage of reducing the risk of aperture obstruction by intermittent differential-pressure-driven flow through each orifice.
Mode 5: Unbalanced delivery and sample flow, with non-zero net fluid volume delivery or sampling. This mode includes the obvious degenerate cases of delivery-only and sample-only operation, but also allows modifications of modes 2, 3 and 4, with the addition of a single-dose or regular repetitive bolus of active material for diagnostic or therapeutic purposes. This mode may be particularly useful for effecting closed-loop control based on information derived from a real-time sensor attached to the microprobe or system.
Some examples of pump flow protocols associated with operating modes 2, 3 and 4 are depicted in
An example of a bolus delivery protocol in operating mode 5 is presented in
Another example of operating mode 5 is presented in
FIG. 6} shows a lumbar puncture application for neurological diagnosis. Current usage (A) removes a considerable volume of cerebrospinal fluid (CSF) for testing. This may cause headache and may be contraindicated in some medical conditions. In contrast, the present invention invention (B) does not need volume removal of CSF for analysis, as it allows the diffusion of large particles, including proteins, cells, bacteria and viruses into carrier fluid in the probe lumen for subsequent analysis.
