SBIR-STTR Award

The objective of this Phase I SBIR proposal is to develop a novel in vivo method for collecting and delivering proteins to the extracellular volume in the central nervous system (CNS). Physiologically significant extracellular proteins include neurotropic factors, cytokines, extracellular enzymes and hormones, of which the pathophysiologic roles are mostly unknown. The immediate application of the proposed method will enable determination of protein function in neurochemical and neuropharmacological research in the brain and spinal cord of whole animals. Potential human applications include drug development and testing, along with clinical diagnostics and drug delivery for alcoholism, Alzheimer's, analgesics, brain tumors, epilepsy, multiple sclerosis and stroke. Specific aims for this novel method are to: 1) develop an optimal LaPP microtube; 2) develop a compatible push-pull microperfusion pump, 3) test the LaPP microtube and push-pull microperfusion pump capability to collect and deliver proteins in vitro. The central element of the technology is a Laser-perforated, Push-Pull Perfused (LAPP) microtube having a protein-exchange zone at the functional end, comprising an array of 10 to 1000 holes of diameters ranging from 1 to 20 microns, and having a bifurcated tubing connection to allow the continuous push-pullregulated perfusion of the outer lumen and inner cannula of the microtube. Semi-automated laser fixturing will be developed to enable fabrication of replicate microtubes having hole arrays of various configurations. In vivo animal experimentation and potential diagnostic applications will be explored in Phase II.

Thesaurus Terms:
brain, drug delivery system, extracellular matrix protein, method development, microdialysis, proteomics catheterization, microtubule, neurochemistry, neuropharmacology, protein transport, sample collection, spinal cord bioengineering /biomedical engineering, biotechnology

The long-term objective of this project is to complete the development a novel technology for collecting and delivering proteins in the brain of freely behaving animals. The central element of this technology is an implantable, Laser-perforated and Push-pull Perfused (LAPP) microprobe. As demonstrated in Phase I, the use of these probes has the potential to monitor, for the first time, dynamic changes in the levels of extracellular proteins, such as inflammatory cytokines and polypeptide hormones, over many months and during various behaviors and disease states. No current technology has this capability. The information generated with this method should be indispensable for understanding the involvement of proteins in the course of neurological disorders. Furthermore, it is inherent to the LAPP technology that it allows not only the collection but, simultaneously, the efficient delivery of proteins and other agents into the extracellular space in brain. As a consequence, LAPP probes will predictably be integrated in future intracranial drug delivery devices for the treatment of otherwise incurable neurological disorders. The first Specific Aim is to perfect the LAPP microprobes and diversify its shape and capacity, so that it can be used for measurements from both the brain tissue and the subdural space. The second Specific Aim is to further refine the accessory push-pull-pump and protein-harvesting systems that are necessary for the use of the probes. In order to satisfy the needs of a broad range of potential users, two versions of this system will be constructed. One can be used on the laboratory bench, whereas the other one will be a miniaturized, telemetry-controlled version portable by the experimental animal. The third Specific Aim is to demonstrate the unique potential of the completed apparatus in an animal experiment. Namely, the LAPP probes will be implanted in the brain of rats, and changes in the extracellular levels of a class of inflammatory proteins called cytokines will be monitored for a full month, before and after the induction of epileptic seizures. The LAPP probes will be manufactured at Lenox Laser, the accessory systems will be developed and the animal studies will be conducted at NYU School of Medicine, and the cytokine measurements will be carried out by RayBiotech, Inc. Neuroscientists, engineers and biochemists will collaborate in order to accomplish the objectives of this enterprise, offering a completely new brain research tool by the end of the project and laying the groundwork for incorporating the developed products in future diagnostic and therapeutic devices. This project will develop a novel, implantable microprobe that is able to efficiently collect and deliver proteins in brain, allowing scientists to reveal the roles of these molecules in such diseases as epilepsy, stroke or AIDS related dementia. This information should help to devise new strategies for the diagnosis and therapy of these, and perhaps other, devastating brain disorders.

Thesaurus Terms:
brain, implant, laser, molecular probe, neurochemistry, protein purification, protein quantitation /detection, technology /technique development central nervous system, computer program /software, computer system hardware electroencephalography, laboratory rat, telemetry