Recent Advances in Polymeric Implants.

Implantable drug delivery systems, such as drug pumps and polymeric drug depots, have emerged as means of providing predetermined drug release profiles at the desired site of action. While initial implants aimed at providing an enduring drug supply, developments in polymer chemistry and pharmaceutical technology and the growing need for refined drug delivery patterns have prompted the design of sophisticated drug delivery implants such as on-demand drug-eluting implants and personalized 3D printed implants. The types of cargo loaded into these implants range from small drug molecules to hormones and even therapeutic cells. This review will shed light upon recent advances in materials and composites used for polymeric implant fabrication, highlight select approaches employed in polymeric implant fabrication, feature medical applications where polymeric implants have a significant impact, and report recent advances made in these areas.

Characterization of Effect of Repeated Bolus or Continuous Intrathecal Infusion of Morphine on Spinal Mass Formation in the Dog.

BACKGROUND: We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs. METHODS: Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.48 mL/day of saline or MS dosing (12 mg/day at 25 mg/mL) as boluses: x1 (q24hour), x2 (q12hour), x4 (q6hour), or x8 (q3hour) given at the rate of 1000 µL/hour, or as a continuous infusion (25 mg/mL/20 µL/hour). RESULTS: With IT saline, minimal pathology was noted. In contrast, animals receiving morphine displayed spinally compressing durally derived masses with the maximal cross-sectional area being greatest near the catheter tip. Histopathology showed that IMs consisted of fibroblasts in a collagen (type 1) matrix comprised of newly formed collagen near the catheter and mature collagen on the periphery of the mass. The rank order of median cross-sectional mass area (mm2 ) was: Saline: 0.7 mm2 ; x2: 1.8 mm2 ; x4: 2.7 mm2 ; x1: 2.7 mm2 ; x8: 4.2 mm2 ; Continuous: 8.1 mm2 , with statistical difference from saline being seen with continuous (p < 0.0001) and x8 (p < 0.05). Bench studies with a 2D diffusion chamber confirmed an increase in dye distribution and lower peak concentrations after bolus delivery versus continuous infusion of dye. CONCLUSIONS: Using multiple bolus dosing, IMs were reduced as compared to continuous infusion, suggesting relevance of bolus delivery in yielding reduced intrathecal masses.

Conversion of Intrathecal Opioids to Fentanyl in Chronic Pain Patients With Implantable Pain Pumps: A Retrospective Study.

OBJECTIVES: Conversion between routes such as intravenous (IV), epidural (EP), and intrathecal (IT) routes for morphine is well established. Conversion ratios for IV:EP:IT fentanyl and conversion from IT morphine/hydromorphone to IT fentanyl have been challenging given the lipophilic nature of fentanyl. Our study reviews the outcomes and conversion ratios reached after converting IT opioids from morphine/hydromorphone to fentanyl in patients with IT pumps. METHODS: After Institutional Review Board approval at Henry Ford Health System, a chart review was performed on all patients who had Synchromed II IT pumps implanted 2009-2016 and were converted from morphine/hydromorphone to fentanyl. The chart review included the initial fentanyl dose and fentanyl IV:IT conversion ratio, eventual IT fentanyl dose, and IV:IT conversion ratio reached to give superior VAS from previous IT opioid. Wilcoxon non-paired signed rank test was used to examine the change in fentanyl dosage and IV:IT conversion ratio. RESULTS: The mean IT morphine equivalent dose at initial conversion was 15.8 mg/day, and the mean fentanyl IT starting dose was 0.73 mg/day (SD = 1.37 mg). The mean fentanyl dose at the end of titration was 0.94 mg/day (SD = 2.05 mg) which represented a significant 25.1% mean dose increase (P = 0.004). The initial mean IV:IT fentanyl conversion ratio was 38.7:1 (SD = 33.01), but the mean IV:IT fentanyl conversion ratio at end of titration with better analgesia was significantly lower at 32.9:1 (SD = 27.1) (P = 0.016). CONCLUSIONS: Given the pharmacokinetics of lipophilic fentanyl compared to hydrophilic morphine/hydromorphone, the current conversion ratio of IV fentanyl to IT fentanyl and IV morphine to IT fentanyl appears to be conservative.

Maximizing Data Transmission Rate for Implantable Devices Over a Single Inductive Link: Methodological Review.

Due to the constantly growing geriatric population and the projected increase of the prevalence of chronic diseases that are refractory to drugs, implantable medical devices (IMDs) such as neurostimulators, endoscopic capsules, artificial retinal prostheses, and brain-machine interfaces are being developed. According to many business forecast firms, the IMD market is expected to grow and they are subject to much research aiming to overcome the numerous challenges of their development. One of these challenges consists of designing a wireless power and data transmission system that has high power efficiency, high data rates, low power consumption, and high robustness against noise. This is in addition to minimal design and implementation complexity. This manuscript concerns a comprehensive survey of the latest techniques used to power up and communicate between an external base station and an IMD. Patient safety considerations related to biological, physical, electromagnetic, and electromagnetic interference concerns for wireless IMDs are also explored. The simultaneous powering and data communication techniques using a single inductive link for both power transfer and bidirectional data communication, including the various data modulation/demodulation techniques, are also reviewed. This review will hopefully contribute to the persistent efforts to implement compact reliable IMDs while lowering their cost and upsurging their benefits.

A Review of Implant Communication Technology in WBAN: Progress and Challenges.

Over the past six decades, there has been tremendous progress made in the field of medical implant communications. A comprehensive review of the progress, current state of the art, and future direction is presented in this paper. Implanted medical devices (IMDs) are designed mainly for the purpose of diagnostic, therapeutic, and assistive applications in heathcare, active living, and sports technology. The primary target of IMDs' design revolves around reliable communications, sustainable power sources, and a high degree of miniaturization while maintaining biocompatibility to surrounding tissues adhering to the human safety limits set by appropriate guidelines. The role of the Internet of Things and intelligent data analysis in implant device networks as future research is presented in this paper. Finally, in addition to reviewing the state of the art, a novel intuitive lower bound on implant size is presented.

Controlled Release of the Nimodipine-Loaded Self-Microemulsion Osmotic Pump Capsules: Development and Characterization.

The present study was intended to develop a controlled released osmotic pump capsule based on Nimodipine (NM)-loaded self-microemulsifying drug delivery systems (SMEDDSs) in order to improve the low oral bioavailability of NM. To optimize the NM-loaded SMEDDS composition, the experiments of NM solubility in different oils, the pseudo-ternary phase diagram experiments and the different drug loading experiments were conducted in the preliminary screening studies. Controlled release of NM required an osmotic pump capsule comprising a coated semi-permeable capsule shell, plasticizer, and pore-forming agent. NM release follows zero-order kinetics after oral administration. Polyethylene glycol content, used as a pore-forming agent, coating mass, and drug release orifice size were key factors affecting drug release behavior according to the single methods and were optimized through response surface methodology. The NM-loaded SMEDDS droplet size and the 1H NMR mass spectrogram of the novel capsule were determined. The droplet size of the reconstituted microemulsion was 39.9 nm and 1H NMR analysis showed NM dissolution in the microemulsion. The dissolution test performed on three batches of NM-SMEDDS capsules-prepared using optimal preparation methods-indicated the capsule to deliver a qualified drug delivery with a zero-order release rate. The results demonstrated that NM-loaded SMEDDSs were successfully developed and displayed a qualified release rate in vitro.

Novel Pump Control Technology Accelerates Drug Delivery Onset in a Model of Pediatric Drug Infusion.

BACKGROUND: Laboratory data suggest that newly initiated drug infusions reach steady-state delivery after a significant time lag. Depending on drug and carrier flow rates and the infusion system's common volume, lag times may exceed 20 or more minutes, especially in the neonatal/pediatric critical care environment. This study tested the hypothesis that a computer-executed algorithm controlling infusion pumps in a coordinated fashion predictably hastens the achievement of the intended steady-state drug delivery in a model of neonatal/pediatric drug infusion. METHODS: We constructed an in vitro model of neonatal/pediatric drug infusions through a pediatric 4-Fr central venous catheter at total system flows of 2 mL/h or 12 mL/h, representing a clinically relevant infusion range. Methylene blue served as the model infused drug for quantitative analysis. A novel algorithm, based on Taylor Dispersion Theory of fluid flow through tubes and executed by a computer, generated flow patterns that controlled and coordinated drug and carrier delivery by syringe pumps. We measured the time to achieve the intended steady-state drug delivery by conventional initiation of the drug infusion ("turning on the drug pump") and by algorithm-controlled infusion initiation. RESULTS: At 2 mL/h total system flow, application of the algorithm reduced the time to achieve half of the intended drug delivery rate (T50) from 17 minutes [17, 18] to 3 minutes [3, 3] (median, interquartile range). At 12 mL/h total system flow, application of the algorithm reduced T50 from 6 minutes [6, 7] to 3 minutes [3, 3] The bootstrapped median difference is -14 (95% confidence interval [CI], -16 to -12, adjusted P=.00192) for 2 mL/h flow and -3 (95% CI, -4 to -3, adjusted P=.02061) for 12 mL/h flow. Compared with conventional initiation, the additional fluid required by the algorithm-directed infusion was 0.43 and 1.03 mL for the low- and high-infusion rates, respectively. CONCLUSIONS: The output of infusion pumps can be predictably controlled and coordinated by a computer-executed algorithm in a model of neonatal/pediatric drug infusions. Application of an algorithm can reduce the time to achieve the intended rate of infused drug delivery with minimal incremental volume administration.

Advanced Implantable Drug Delivery Systems via Continuous Manufacturing.

Polymeric implantable drug delivery systems have remarkable potential for systemic delivery of various therapeutic agents. Generally, drug-loaded implants do not require a vehicle for delivery and can be used to attain prolonged delivery into the systemic circulation of active pharmaceutical ingredients (APIs) with enhanced drug bioavailability. Furthermore, implants can provide drug release ranging from months to years, which improves patient compliance, especially for poorly bioavailable and rapidly metabolized compounds. Continuous manufacturing technology (e.g., hot-melt extrusion, or HME) has been successfully employed to prepare drug-loaded single-unit polymeric implants. Employing heat and mechanical shear, such systems retain the stability of thermolabile therapeutics (e.g., proteins) in implants. HME has emerged as important because of its varied applications that combine economic viability with solvent-free and easy scale-up processing. Moreover, it has been recognized from a quality-by-design (QbD) viewpoint by the FDA.

Miocardiopatía dilatada idiopática tratada con infusión intracoronaria de células autólogas de médula ósea: seguimiento a largo plazo / Idiopathic dilated cardiomyopathy treated with intracoronary infusion of autologous bone marrow cells: long-term follow-up

No disponible

Diabetes Device Interoperability for Improved Diabetes Management.

Scientific and technological advancements have led to the increasing availability and use of sophisticated devices for diabetes management, with corresponding improvements in public health. These devices are often capable of sharing data with a few other specific devices but are generally not broadly interoperable; they cannot work together with a wide variety of other devices. As a result of limited interoperability, benefits of modern diabetes devices and potential for development of innovative new diabetes technologies are not being fully realized. Here we discuss diabetes device interoperability in general, then focus on 4 examples that show how diabetes management could benefit from enhanced interoperability: remote monitoring and data sharing, integrating data from multiple devices to better inform diabetes management strategies, device consolidation, and artificial pancreas development.

Surgical Site Infection 18 Months Following Intrathecal Pump Placement Secondary to an Asymptomatic Bowel Injury.

Surgical site infections following the implantation of intrathecal drug delivery systems typically present during the first 1 to 2 months following surgery. Surgical site infections occurring outside of this window are rare entities and require special attention to identify the source or underlying cause. In this report, we present a case of pump pocket infection 18 months following implantation due to an asymptomatic and unrecognized bowel injury associated with the catheter. This case highlights the need for a thorough evaluation in a patient with suspected infections more than 2 months after surgery to ensure adequate treatment.

[Development possibilities of hormone-containing implants for gynecological applications: A review]. / Nogyógyászati célra szánt, hormontartalmú implantátumok fejlesztési lehetoségeinek áttekintése: irodalmi áttekintés.

Implantable gynecological drug delivery devices are applied for contraceptive, hormone replacement purposes and for the treatments of other gynecological diseases, e.g. endometriosis. The review provides a comprehensive overview about the indications, advantages, limitation of application and the applied technologies of hormone-containing implants, as well. The study comprises the relevant patents and the recently published papers.

Insulin therapy: going the "smarter" way.

Insulin pharmacology has evolved from nonhuman source based extraction of insulin, to use of recombinant technologies for human insulin production, to tailor made synthetic insulin analogues. The delivery techniques of insulin have also improved, from injections to pumps, and to pumps with sensors. However, to achieve the final goal of a closed loop insulin delivery is far from achieved. One of the researches in this direction includes synthetic smart insulins. These are systems with chemical sensors for glucose, linked to reactions that trigger glucose mediated insulin delivery. Interest in this field is high and recent publications and patents show promise. The current review tries to summarize the basic concept of smart insulin as well as cater the recent developments and patents in this direction.

Closed-loop artificial pancreas: current studies and promise for the future.

PURPOSE OF REVIEW: The availability of glucose sensors and insulin pumps has enabled the development of devices and software to partially or completely automate insulin delivery. Over the last 2 years, the number of centers developing and evaluating such systems, as well as the number of reports of these studies in the literature, have expanded dramatically. The purpose of this review is to highlight the progress along multiple fronts to develop automated systems to improve control of type 1 diabetes. RECENT FINDINGS: Multiple approaches, including automated suspension for actual or impending hypoglycemia, automated augmentation for hyperglycemia, as well as hybrid and full closed-loop control, are in parallel development. So far, early hypoglycemia prevention studies and small inpatient feasibility studies have demonstrated the potential for reducing hypoglycemia and improving overall diabetes control. SUMMARY: Current sensors, pumps, and control algorithms show promise for use in a closed-loop system but have been limited to inpatient studies. The next phase of development should focus on their evaluation in controlled short-term outpatient safety and efficacy trials.