Programmable Drug Delivery System Research Articles

ID: 214681 Longitudinal Data From the Targeted Drug Delivery (TDD) Product Surveillance Registry: Pump Pocket Location

TDD with programmable intrathecal drug delivery systems (IDDS) has been approved for chronic malignant and nonmalignant pain treatment since 1991 and severe spasticity since 1992. Early clinical IDDS studies specified an “abdominal pocket” as the pump implant location, resulting in this as the defined on-label location. Alternate pump pocket locations are preferred by some implanting physicians for patient-specific reasons, but full evaluation of the risks and benefits of these alternate pump sites has not been performed. Presented here is an evaluation of real-world registry data on the potential risks and benefits of 7415 pump implants.

ID: 215569 Updated Longitudinal Data From IDDS Product Surveillance Registry: Effect of Pump Durable Design Changes

TDD with programmable intrathecal drug delivery systems (IDDS) has been approved for malignant and chronic nonmalignant pain treatment since 1991 and severe spasticity since 1992. Identification of rare product performance events within IDDS becomes possible with expanded clinical use, necessitating product modifications to mitigate patient risk. Presented here is real-world evaluation of product performance updated with the most recent data following release of an enhanced IDDS.

ID: 216262 Longitudinal Data From the Targeted Drug Delivery (TDD) Product Surveillance Registry: Inflammatory Mass

TDD with programmable intrathecal drug delivery systems (IDDS) has been approved for chronic malignant and nonmalignant pain treatment since 1991 and severe spasticity since 1992. Intrathecal inflammatory mass (IM) is a known risk of intrathecally delivered opioid compound. IM’s, or granulomas, are sterile masses that develop proximal to the intrathecal (IT) catheter tip, consisting of inflammatory cells and fibroblasts. Rates of IM have been decreasing over time. We conjecture that this is due to education, research, and changes in clinical practice with reduction of drug concentrations and dosing.

PO203 / #915 LONGITUDINAL DATA FROM THE TARGETED DRUG DELIVERY (TDD) PRODUCT SURVEILLANCE REGISTRY: PUMP POCKET LOCATION: E-POSTER VIEWING

TDD with programmable intrathecal drug delivery systems (IDDS) has been approved for cancer and noncancer pain treatment since 1991 and severe spasticity since 1992. Early clinical IDDS studies specified an “abdominal pocket” as the pump implant location, resulting in this as the defined on-label location. Alternate pump implant locations are often necessary for patient-specific reasons, but full evaluation of the risks and benefits of these alternate pump sites has not been performed. Presented here is an evaluation of real-world registry data on the potential risks and benefits of alternate pump implant locations.

Shape-Programmable Three-Dimensional Microfluidic Structures.

Microfluidic devices are gaining extensive interest due to their potential applications in wide-ranging areas, including lab-on-a-chip devices, fluid delivery, and artificial vascular networks. Most current microfluidic devices are in a planar design with fixed configurations once formed, which limits their applications such as in engineered vascular networks in biology and programmable drug delivery systems. Here, shape-programmable three-dimensional (3D) microfluidic structures, which are assembled from a bilayer of channel-embedded polydimethylsiloxane (PDMS) and shape-memory polymers (SMPs) via compressive buckling, are reported. 3D microfluidics in diverse geometries including those in open-mesh configurations are presented. In addition, they can be programmed into temporary shapes and recover their original shape under thermal stimuli due to the shape memory effect of the SMP component, with fluid flow in the microfluidic channels well maintained in both deformed and recovered shapes. Furthermore, the shape-fixing effect of SMPs enables freestanding open-mesh 3D microfluidic structures without the need for a substrate to maintain the 3D shape as used in previous studies. By adding magnetic particles into the PDMS layer, magnetically responsive 3D microfluidic structures are enabled to achieve fast, remote programming of the structures via a portable magnet. A 3D design phase diagram is constructed to show the effects of the magnetic PDMS/SMP thickness ratio and the volume fraction of magnetic particles on the shape programmability of the 3D microfluidic structures. The developed shape-programmable, open-mesh 3D microfluidic structures offer many opportunities for applications including tissue engineering, drug delivery, and many others.

Modeling programmable drug delivery in bioelectronics with electrochemical actuation.

Drug delivery systems featuring electrochemical actuation represent an emerging class of biomedical technology with programmable volume/flowrate capabilities for localized delivery. Recent work establishes applications in neuroscience experiments involving small animals in the context of pharmacological response. However, for programmable delivery, the available flowrate control and delivery time models fail to consider key variables of the drug delivery system--microfluidic resistance and membrane stiffness. Here we establish an analytical model that accounts for the missing variables and provides a scalable understanding of each variable influence in the physics of delivery process (i.e., maximum flowrate, delivery time). This analytical model accounts for the key parameters--initial environmental pressure, initial volume, microfluidic resistance, flexible membrane, current, and temperature--to control the delivery and bypasses numerical simulations allowing faster system optimization for different in vivo experiments. We show that the delivery process is controlled by three nondimensional parameters, and the volume/flowrate results from the proposed analytical model agree with the numerical results and experiments. These results have relevance to the many emerging applications of programmable delivery in clinical studies within the neuroscience and broader biomedical communities.

Mechano-activated biomolecule release in regenerating load-bearing tissue microenvironments

Although mechanical loads are integral for musculoskeletal tissue homeostasis, overloading and traumatic events can result in tissue injury. Conventional drug delivery approaches for musculoskeletal tissue repair employ localized drug injections. However, rapid drug clearance and inadequate synchronization of molecule provision with healing progression render these methods ineffective. To overcome this, a programmable mechanoresponsive drug delivery system was developed that utilizes the mechanical environment of the tissue during rehabilitation (for example, during cartilage repair) to trigger biomolecule provision. For this, a suite of mechanically-activated microcapsules (MAMCs) with different rupture profiles was generated in a single fabrication batch via osmotic annealing of double emulsions. MAMC physical dimensions were found to dictate mechano-activation in 2D and 3D environments and their stability in vitro and in vivo, demonstrating the tunability of this system. In models of cartilage regeneration, MAMCs did not interfere with tissue growth and activated depending on the mechanical properties of the regenerating tissue. Finally, biologically active anti-inflammatory agents were encapsulated and released from MAMCs, which counteracted degradative cues and prevented the loss of matrix in living tissue environments. This unique technology has tremendous potential for implementation across a wide array of musculoskeletal conditions for enhanced repair of load-bearing tissues.

Advances in Biomimetic Systems for Molecular Recognition and Biosensing.

Understanding the fundamentals of natural design, structure, and function has pushed the limits of current knowledge and has enabled us to transfer knowledge from the bench to the market as a product. In particular, biomimicry―one of the crucial strategies in this respect―has allowed researchers to tackle major challenges in the disciplines of engineering, biology, physics, materials science, and medicine. It has an enormous impact on these fields with pivotal applications, which are not limited to the applications of biocompatible tooth implants, programmable drug delivery systems, biocompatible tissue scaffolds, organ-on-a-chip systems, wearable platforms, molecularly imprinted polymers (MIPs), and smart biosensors. Among them, MIPs provide a versatile strategy to imitate the procedure of molecular recognition precisely, creating structural fingerprint replicas of molecules for biorecognition studies. Owing to their affordability, easy-to-fabricate/use features, stability, specificity, and multiplexing capabilities, host-guest recognition systems have largely benefitted from the MIP strategy. This review article is structured with four major points: (i) determining the requirement of biomimetic systems and denoting multiple examples in this manner; (ii) introducing the molecular imprinting method and reviewing recent literature to elaborate the power and impact of MIPs on a variety of scientific and industrial fields; (iii) exemplifying the MIP-integrated systems, i.e., chromatographic systems, lab-on-a-chip systems, and sensor systems; and (iv) closing remarks.

Programmable antibiotic delivery to combat methicillin-resistant Staphylococcus aureus through precision therapy

The rapid dissemination of life-threatening multidrug-resistant bacterial pathogens calls for the development of new antibacterial agents and alternative strategies. The virulence factor secreted by bacteria plays a crucial role in the sophisticated processes during infections. Inspired by the unique capacity of many bacteria inducing clotting of plasma to initiate colonization, we propose a programmable antibiotic delivery system for precision therapy using methicillin-resistant S. aureus (MRSA) as a model. Coagulase utilized by MRSA to directly cleave fibrinogen into fibrin, is an ideal target not only for tracking bacterial status but for triggering the collapse of fibrinogen functionalized porous microspheres. Subsequently, staphylokinase, another virulence factor of MRSA, catalyzed hydrolysis of fibrin to further release the encapsulated antibiotics from microspheres. Our sequential triggered-release system exhibits high selectivity to distinguish live or dead MRSA from other pathogenic bacteria. Furthermore, such programmable microspheres clear 99% MRSA in 4 h, and show increased efficiency in a wound healing model in rats. Our study provides a programmable drug delivery system to precisely target bacterial pathogens using their intrinsic enzymatic cascades. This programmable platform with reduced selective stress of antibiotics on microbiota sheds light on the potential therapy for future clinical applications.

Designer DNA-silica/carbon nanotube nanocomposites for traceable and targeted drug delivery.

Due to their unique properties like porosity, high water content, softness and biocompatibility, hydrogels are of great interest for biomedical applications such as tissue engineering and drug delivery. We describe a programmable drug delivery system that is based on highly biocompatible SiNP/CNT-DNA nanocomposites, which can be synthesized in a highly modular fashion from DNA-functionalized carbon nanotubes and silica nanoparticles via enzymatic rolling circle amplification. Specific molecular recognition properties were implemented into the materials by DNA sequence design, as demonstrated by incorporation of GC/CG-rich stem loop and aptamer motifs that enable selective binding of intercalating drugs and cell surface receptors, respectively. In a proof-of-concept study we demonstrate the utility of this approach by targeting nanocomposites loaded with the anthracycline drug doxorubicin to HeLa cancer cells. Our observation that these designer materials work more efficiently than the pure drug alone suggests that further developments of the concept might be useful to selectively trigger more complex cellular pathways.

A nanoliter resolution implantable micropump for murine inner ear drug delivery

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. Here we present results for a novel biocompatible, implantable, scalable, and wirelessly controlled peristaltic micropump. The micropump configuration included commercially available catheter microtubing (250 μm OD, 125 μm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Peristaltic pumping was achieved by sequentially compressing the microtubing via expansion and contraction of a thermal phase-change material located in three chambers integrated adjacent to the microtubing. Direct-write micro-scale printing technology was used to build the mechanical components of the micropump around the microtubing directly on the back of a printed circuit board assembly (PCBA). The custom PCBA was fabricated using standard commercial processes providing microprocessor control of actuation and Bluetooth wireless communication through an Android application. The results of in vitro characterization indicated that nanoliter resolution control over the desired flow rates of 10–100 nL/min was obtained by changing the actuation frequency. Applying 10× greater than physiological backpressures and ± 3 °C ambient temperature variation did not significantly affect flow rates. Three different micropumps were tested on six mice for in vivo implantation of the catheter microtubing into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. There were systematic increases in distortion product threshold shifts during the 20-min perfusions; the mean shift was 15 dB for the most basal region. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. The results indicated that the micropump components successfully passed key biocompatibility tests. A micropump prototype was implanted for one month without development of inflammation or infection. Although tested here on the small murine cochlea, this low-cost design and fabrication methodology is scalable for use in larger animals and for clinical applications in children and adults by appropriate scaling of the microtubing diameter and actuator volume.

A CD44-Targeting Programmable Drug Delivery System for Enhancing and Sensitizing Chemotherapy to Drug-Resistant Cancer.

Programmable drug delivery systems hold great promise to enhance cancer treatment. Herein, a programmable drug delivery system using a chondroitin sulfate (CS)-based composite nanoparticle was developed for enhancing and sensitizing chemotherapy to drug-resistant cancer. The nanoparticle was composed of a cross-linked CS hydrogel shell and hydrophobic cores containing both free drugs and CS-linked prodrugs. Interestingly, the nanoparticle could mediate tumor-specific CD44 targeting. After specific cellular uptake, the payloads were suddenly released because of the decomposition of the CS shell, and the free drug molecules with synergistic effects induced tumor-specific cytotoxicity rapidly. Subsequently, the inner cores of the nanoparticles sustainedly release their cargos in drug-resistant tumor cells to keep the effective drug concentration against the drug efflux mediated by P-glycoprotein. CS dissociated from the outer shell and sensitized cancer cells to the antitumor drugs through downregulation of Bcl-XL, an antiapoptosis protein. Such a programmable drug delivery system with specific tumor-targeting and sensitized therapy is promising for rational drug delivery and provides more versatility for controlled release in biomedical applications.

적층 제조 기술을 이용한 지능형 약물 전달 시스템의 개발

A programmable drug delivery system can control the release rate of a drug. It can minimize side effects while maximizing therapeutic effects. In this research, we investigated the feasibility of producing a programmable drug delivery system using 3D printing technology. A capsule with a micro-orifice and a drug-laden hydrogel was designed. The designed system was then fabricated by the printing process using polycaprolactone and hydrogel. The printed drug delivery system was immersed in PBS at 37°C and the number of molecules released was measured thorough colorimetric analysis. The effect of diameter and length of the micro-orifice and concentration of the hydrogel on drug release characteristics was then determined. The initial burst release rate was found to be increased with increasing orifice size. Increasing the length of the orifice linearly delayed the start time of drug release. At length of 600 μm and 1,200 μm, drug release was initiated after 36 h and 72 h for, respectively. When the concentration of hydrogel was increased, drug release rate tended to decrease. These results successfully confirmed that a drug delivery system with controlled release rate and initiation time could be manufactured using 3D printing technology.

Targeted cowpea chlorotic mottle virus-based nanoparticles with tumor-homing peptide F3 for photothermal therapy

Our aim was to devise targeted drug delivery systems using genetically modified cowpea chlorotic mottle virus (CCMV) capsids by fusion expression with tumorhoming peptide F3 for efficient delivery of therapeutic substances into tumor cells. The RNA-binding domain at the N terminus (amino acid residues 1–25) of CCMV capsid protein (CP) was selectively deleted, and F3 was inserted for the expression in Pichia pastoris. After chromatographic purification, F3-CCMV capsids were obtained via selfassembly of the F3-CP fusion protein and then analyzed by transmission electron microscopy and dynamic light scattering analysis, which revealed spherical nanoparticles (NPs) ca. 18 nm in diameter with regular monodispersity. Near-infrared fluorescent dye IR780 iodide, which has been applied for cancer imaging, photodynamic therapy, and photothermal therapy, was encapsulated in F3-CCMV NPs. The resultant F3-CCMV-IR780 NPs showed excellent molecular targeting to nucleolin receptor overexpressed on the surface of MCF-7 tumor cells. Furthermore, the in vitro cellular uptake and cell viability assay proved a photothermal effect by a single dose of near-infrared laser irradiation. The present system may offer a programmable nanoscaffoldbased drug delivery system vehicle for fabrication of promising therapeutic substances for cancer therapy.

Tailored design of multifunctional and programmable pH-responsive self-assembling polypeptides as drug delivery nanocarrier for cancer therapy.

This tailored-design polypeptide-based nanoparticles with self-assembling and programmable stimulus-responsive properties enable to 1) have stable pH in physiological value with a low level of drug loss and effectively release the encapsulated drug with pH variations according to the tumor microenvironment, 2) enhance targeting ability to hard-to-treat breast cancer cells and activate endothelial cells (tumor region), 3) significantly inhibit the growth and prevent from malignant metastasis of cancer cells in consonance with promising anti-tumor efficacy, and 4) make tumors stick to localized position so that these confined solid tumors can be more accessible by different treatment modalities. This work contributes to designing a programmable pH-responsive drug delivery system based on the tailor-designed polypeptides.

Programmable intrathecal pumps for the management of chronic pain: recommendations for improved efficiency.

The management of chronic pain can be very challenging. Often, physicians employ intrathecal (IT) drug delivery systems as a last resort to relieve intractable pain. The system consists of an implantable pump that stores and delivers medication through a catheter to the IT space. Programmability is achieved by positioning an external devise over the implanted pump to change the mode of drug delivery. The innovations in programmable IT drug delivery systems are expanding more rapidly than ever before. Unfortunately, the rapid expansion is accompanied by a lack of prospective randomized trials examining these new options. In an effort to improve results and reduce side effects, publications by experts or expert consensus panels provide guidance for the community. The purpose of this article is to provide a summary of high interest topics in recent publications.

Efficacy of intrathecal drug delivery system for refractory cancer pain patients: A single tertiary medical center experience

Between 10% and 20% of cancer pain patients fail to obtain adequate pain relief despite comprehensive medical management. The totally implantable programmable intrathecal drug delivery system (IDDS) is an attractive option for managing refractory cancer pain. In suitable patients, IDDS can provide reliable long-term analgesia without any permanent nerve or plexus destruction. IDDS can also allow patient care on an outpatient basis. In Taiwan, however, the experience of using IDDS in terminally ill cancer patients is very limited. This retrospective study, describes experience of managing totally implantable programmable IDDS in 6 refractory cancer pain patients including patient selection, intraspinal morphine trial, surgical techniques, complications, and drug adjustment. Pain scores and functional status were compared before and after IDDS. By delivering liberal dose of intrathecal morphine, patients' pain scores decreased from 10 to 3.5. Due to much better pain control and improved quality of life, Eastern Cooperative Oncology Group performance status also improved in 4/6 patients. During the mean 5±4.1 months of follow-up, two patients experienced pocket seroma, and resolved spontaneously after short-term abdominal binder compression. Otherwise, no serious complication was noted. Intrathecal morphine delivery by using totally implantable programmable IDDS is an effective method to relieve refractory cancer pain.

The Safety of Magnetic Resonance Imaging in Patients with Programmable Implanted Intrathecal Drug Delivery Systems

It is common clinical practice to perform magnetic resonance imaging (MRI) in patients with indwelling programmable intrathecal drug delivery (IDD) systems, although the safety of the procedure has never been documented. We performed a single-center, 3-year, prospective evaluation in patients with a programmable implanted IDD to assess patient discomfort, IDD technical failures, and adverse effects during and after exposure to MRI. Forty-three consecutive patients with an implanted programmable IDD system (SynchroMed® EL Implantable Infusion Pump, Model 8626L-18, and SynchroMed® II Model 8637-20, 8637-40; Medtronic, Inc., Minneapolis, MN) requiring a scheduled MRI evaluation were studied during a 3-year period. All MRI scans were performed with a 1.5-tesla clinical use magnet and a specific absorption rate of no more than 0.9 W/kg. Radiograph control was used to confirm postexposure pump rotor movement and detect system dislocations. IDD system failures, patient satisfaction, and discomfort were recorded. None of the patients experienced signs of drug overinfusion that could lead to hemodynamic, respiratory, or neurologic alterations. Radiologic evaluation after MRI revealed no spatial displacements of the intrathecal catheter tip or body pump, and programmer telemetry confirmed the infusion recovery. Patients' satisfaction after the procedure was high. Performing an MRI scan with the proposed protocol in patients with an implanted Medtronic programmable IDD system resulted in virtually no technical or medical complications.

Carbon Nanotube Membranes for use in the Transdermal Treatment of Nicotine Addiction and Opioid Withdrawal Symptoms

Transdermal systems are attractive methods of drug administration specifically when treating patients for drug addiction. Current systems however are deficient in therapies that allow variable flux values of drug, such as nicotine for smoking cessation or complex dosing regimens using clonidine when treating opioid withdrawal symptoms. Through the use of functionalized carbon nanotube (CNT) membranes, drug delivery to the skin can be controlled by applying a small electrical bias to create a programmable drug delivery system. Clearly, a transdermal patch system that can be tailored to an individual's needs will increase patient compliance as well as provide much more efficient therapy. The purpose of this paper is to discuss the applicability of using carbon nanotube membranes in transdermal systems for treatment of drug abuse.

Radiculalgie après implantation de pompe à baclofène

Introduction Intrathecally delivered baclofen has been used as a treatment for severe spasticity since 1984. After a successful intrathecal baclofen trial, a programmable drug delivery system was implanted. Few early complications such as infection or hematoma are observed after this surgery. Objective To describe an unusual and unknown complication of intrathecal baclofen therapy. Method: We report 2 cases of complications of intrathecal baclofen therapy, radiculalgy, that appeared early after pump implantation. The clinical symptoms and computed tomography (CT) results are described. Results The first patient described pain, which evoked left S1 radiculopathic features. The second had left L5 radiculopathic involvement. The mean pain level was estimated on a 10-point visual analog scale as 7.5 (range 4–9). Lumbar CT scan showed a conflict between the symptomatic root and the catheter and eliminated other causes of the symptoms. Treatment with analgesic drugs was successful in 1 patient. The other presented with proximal disconnection of the catheter, which led to surgical replacement of the catheter. The pain disappeared after this surgery. Conclusion Intrathecal baclofen therapy with a subcutaneously implanted progammable pump can be complicated by radiculalgy secondary to a conflict between the catheter and symptomatic root. The diagnosis is made by CT lumbar scan. If medical treatment is not sufficient, surgery could be proposed to replace the catheter.