Focal, remote-controlled, chronic chemical modulation of brain microstructures

Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients. Keywords: brain; drug delivery; substantia nigra; neural implant; PETNational Institutes of Health (U.S.) (Grant R01 EB016101)National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant R01 EB016101)National Cancer Institute (U.S.) (Grant P30-CA14051

Single Subcompartment Drug Delivery

Most drugs are administered systemically, intravenously or orally, but there are inherent challenges with these methods. Drug distributes throughout the body, which results in two main challenges: (1) poor efficacy due to the under accumulation of drug at sites of disease and (2) side effects due to the over accumulation of drug in healthy tissue where the drug may interact with off-target molecules or cells. Several strategies have been developed to improve drug distribution. Nanoparticles and antibody-drug conjugates use targeting molecules to increase drug accumulation at certain sites or cells, leading to improved outcomes, but only a handful of such therapies have had a clinical impact thus far or do not work for all indications. Further advancements have also been made to change the administration route of drugs rather than relying on molecular targeting. The body can be broken down into a series of compartments that encompass different cavities or organ systems, such as the peritoneum, urinary tract, or eye. Drugs can be directly delivered to a single compartment through an infusion system or drug-eluting implant. Single compartment drug delivery increases drug concentration at the target site and minimizes drug exposure at distant sites of the body, leading to improved outcomes and reduced side effects. Several such strategies have successfully been commercialized. Improved understanding of physiology and disease progression at the cellular and molecular level has led to further defining of disease pathology beyond the single compartment. The brain, for example, has been divided into several microstructures, each of which has a different function that can be disrupted leading to disease. Tumors have also been further defined as separate entities from healthy organs due to genetic, immune, and microenvironment variations. We hypothesize that targeting single subcompartments can further advance single compartment drug delivery strategies. We present novel examples of single subcompartment drug delivery devices for treating and diagnosing disease. Chronic brain implants were developed to elicit minimal scarring and deliver microliters of drug to distinct microstructures suspect in disease, such as a seizure focus. An implant and computational platform was further developed to deliver drug microdoses to tumor, analyze the tumor response to each drug, and computationally predict potential efficacy of each drug. This platform successfully predicted systemic treatment outcomes in ovarian patient-derived xenograft tumors with greater than 90% accuracy, with the potential for clinical implementation in the near-term. The results of both studies represent the promise of single subcompartment drug delivery to improve outcomes for patients.Ph.D

Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices

Treatments for neurologic diseases are often limited in efficacy due to poor spatial and temporal control over their delivery. Intracerebral delivery partially overcomes this by directly infusing therapeutics to the brain. Brain structures, however, are nonuniform and irregularly shaped, precluding complete target coverage by a single bolus without significant off-target effects and possible toxicity. Nearly complete coverage is crucial for effective modulation of these structures. We present a framework with computational mapping algorithms for neural drug delivery (COMMAND) to guide multi-bolus targeting of brain structures that maximizes coverage and minimizes off-target leakage. Custom-fabricated chronic neural implants leverage rational fluidic design to achieve multi-bolus delivery in rodents through a single infusion of radioactive tracer (Cu-64). The resulting spatial distributions replicate computed spatial coverage with 5% error in vivo, as detected by positron emission tomography. COMMAND potentially enables accurate, efficacious targeting of discrete brain regions.National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant R01 EB016101)National Cancer Institute (U.S.) (Grant P30-CA14051

Machine-learning aided in situ drug sensitivity screening predicts treatment outcomes in ovarian PDX tumors

Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility. We describe a drug sensitivity screening assay using a drug delivery microdevice implanted for 24 h in subcutaneous (SQ) ovarian PDX tumors to predict treatment outcomes in matched IP PDX tumors in a clinically relevant time frame. The SQ tumor response to local microdose drug exposure was found to be predictive of the growth of matched IP tumors after multi-week systemic therapy using significantly fewer animals (10 SQ vs 206 IP). Multiplexed immunofluorescence image analysis of phenotypic tumor response combined with a machine learning classifier could predict IP treatment outcomes against three second-line cytotoxic therapies with an average AUC of 0.91

Platform for micro-invasive membrane-free biochemical sampling of brain interstitial fluid

Neurochemical dysregulation underlies many pathologies and can be monitored by measuring the composition of brain interstitial fluid (ISF). Existing in vivo tools for sampling ISF do not enable measuring large rare molecules, such as proteins and neuropeptides, and thus cannot generate a complete picture of the neurochemical connectome. Our micro-invasive platform, composed of a nanofluidic pump coupled to a membrane-free probe, enables sampling multiple neural biomarkers in parallel. This platform outperforms the state of the art in low-flow pumps by offering low volume control (single stroke volumes, <3 nl) and bidirectional fluid flow (<100 nl/min) with negligible dead volume (<30 nl) and has been validated in vitro, ex vivo, and in vivo in rodents. ISF samples (<1.5 μL) can be processed via liquid chromatography-tandem mass spectrometry. These label-free liquid biopsies of the brain could yield a deeper understanding of the onset, mechanism, and progression of diverse neural pathologies.National Institute of Biomedical Imaging and Bioengineering (Grants R01 EB016101, R01 EB027717-01A1)NSF (Grant 2016220817