Implantable Drug Delivery Systems Research Articles

Implantable Drug Delivery Systems and Foreign Body Reaction: Traversing the Current Clinical Landscape.

Precise delivery of therapeutics to the target structures is essential for treatment efficiency and safety. Drug administration via conventional routes requires overcoming multiple transport barriers to achieve and maintain the local drug concentration and commonly results in unwanted off-target effects. Patients’ compliance with the treatment schedule remains another challenge. Implantable drug delivery systems (IDDSs) provide a way to solve these problems. IDDSs are bioengineering devices surgically placed inside the patient’s tissues to avoid first-pass metabolism and reduce the systemic toxicity of the drug by eluting the therapeutic payload in the vicinity of the target tissues. IDDSs present an impressive example of successful translation of the research and engineering findings to the patient’s bedside. It is envisaged that the IDDS technologies will grow exponentially in the coming years. However, to pave the way for this progress, it is essential to learn lessons from the past and present of IDDSs clinical applications. The efficiency and safety of the drug-eluting implants depend on the interactions between the device and the hosting tissues. In this review, we address this need and analyze the clinical landscape of the FDA-approved IDDSs applications in the context of the foreign body reaction, a key aspect of implant–tissue integration.

Fused deposition modelling 3D printing proof-of-concept study for personalised inner ear therapy.

There is a requirement within ear therapeutics for a delivery system capable of safely delivering controlled doses to the inner ear. However, the anatomy and sensitivity of the inner ear make current delivery systems problematic and often ineffective. Therefore, a new delivery system is required to overcome these issues and provide a more efficacious system in the treatment of inner ear disease. This study assesses the potential of 3D printing (3DP) as a fabrication method for an implantable drug delivery system (DDS) to the inner ear. Three implantable designs of varying geometry were produced with fused deposition modelling (FDM) 3DP, each loaded with 0.25%, 0.5% and 1% levofloxacin; filaments prepared by hot-melt extrusion. Each implant was effective in providing sustained, therapeutic release of levofloxacin for at least 4 days and as such would be effective in therapeutic treatment of many common inner ear diseases, such as otitis media or Ménière's disease. This proof-of-concept research was successful in utilising FDM as a fabrication method for a DDS capable of providing prolonged release directly to the inner ear and highlights the viability of 3DP in the fabrication of an inner ear DDS.

Biomimetic cell-actuated artificial muscle with nanofibrous bundles

Biohybrid artificial muscle produced by integrating living muscle cells and their scaffolds with free movement in vivo is promising for advanced biomedical applications, including cell-based microrobotic systems and therapeutic drug delivery systems. Herein, we provide a biohybrid artificial muscle constructed by integrating living muscle cells and their scaffolds, inspired by bundled myofilaments in skeletal muscle. First, a bundled biohybrid artificial muscle was fabricated by the integration of skeletal muscle cells and hydrophilic polyurethane (HPU)/carbon nanotube (CNT) nanofibers into a fiber shape similar to that of natural skeletal muscle. The HPU/CNT nanofibers provided a stretchable basic backbone of the 3-dimensional fiber structure, which is similar to actin-myosin scaffolds. The incorporated skeletal muscle fibers contribute to the actuation of biohybrid artificial muscle. In fact, electrical field stimulation reversibly leads to the contraction of biohybrid artificial muscle. Therefore, the current development of cell-actuated artificial muscle provides great potential for energy delivery systems as actuators for implantable medibot movement and drug delivery systems. Moreover, the innervation of the biohybrid artificial muscle with motor neurons is of great interest for human-machine interfaces.

Local Delivery of Pirfenidone by PLA Implants Modifies Foreign Body Reaction and Prevents Fibrosis.

Peri-implant fibrosis (PIF) increases the postsurgical risks after implantation and limits the efficacy of the implantable drug delivery systems (IDDS). Pirfenidone (PF) is an oral anti-fibrotic drug with a short (<3 h) circulation half-life and strong adverse side effects. In the current study, disk-shaped IDDS prototype combining polylactic acid (PLA) and PF, PLA@PF, with prolonged (~3 days) PF release (in vitro) was prepared. The effects of the PLA@PF implants on PIF were examined in the rabbit ear skin pocket model on postoperative days (POD) 30 and 60. Matching blank PLA implants (PLA0) and PLA0 with an equivalent single-dose PF injection performed on POD0 (PLA0+injPF) served as control. On POD30, the intergroup differences were observed in α-SMA, iNOS and arginase-1 expressions in PLA@PF and PLA0+injPF groups vs. PLA0. On POD60, PIF was significantly reduced in PLA@PF group. The peri-implant tissue thickness decreased (532 ± 98 μm vs. >1100 μm in control groups) approaching the intact derma thickness value (302 ± 15 μm). In PLA@PF group, the implant biodegradation developed faster, while arginase-1 expression was suppressed in comparison with other groups. This study proves the feasibility of the local control of fibrotic response on implants via modulation of foreign body reaction with slowly biodegradable PF-loaded IDDS.

Silicon Carbide-Gated Nanofluidic Membrane for Active Control of Electrokinetic Ionic Transport.

Manipulation of ions and molecules by external control at the nanoscale is highly relevant to biomedical applications. We report a biocompatible electrode-embedded nanofluidic channel membrane designed for electrofluidic applications such as ionic field-effect transistors for implantable drug-delivery systems. Our nanofluidic membrane includes a polysilicon electrode electrically isolated by amorphous silicon carbide (a-SiC). The nanochannel gating performance was experimentally investigated based on the current-voltage (I-V) characteristics, leakage current, and power consumption in potassium chloride (KCl) electrolyte. We observed significant modulation of ionic diffusive transport of both positively and negatively charged ions under physical confinement of nanochannels, with low power consumption. To study the physical mechanism associated with the gating performance, we performed electrochemical impedance spectroscopy. The results showed that the flat band voltage and density of states were significantly low. In light of its remarkable performance in terms of ionic modulation and low power consumption, this new biocompatible nanofluidic membrane could lead to a new class of silicon implantable nanofluidic systems for tunable drug delivery and personalized medicine.

Anesthetic considerations in patients with implantable devices and chronic pain surgery

The use of advanced invasive techniques for the control of chronic pain in patients with multiple comorbidities is becoming increasingly common. Neuromodulation offers a new management alternative involving the infusion of one or more drugs into the epidural or intrathecal space through a fully implantable infusion pump. It also involves spinal stimulation, a minimally invasive technique in which electrodes are positioned in the epidural space and connected to a pulse generator that is implanted subcutaneously and generates pulses designed to suppress the noxious stimulus. This article will describe the anesthetic considerations in cases of implantable drug delivery systems, and spinal and peripheral nerve stimulation devices. Additionally, patients with electrical or drug neuromodulation devices may present to anesthetic practice for surgical indications unrelated to their chronic pain pathology. Hence the importance of being familiar with the basic components of these devices, how they work, what drugs they use and the potential associated complications in the perioperative context, in order to ensure proper management and patient safety.

Wearable Glucose Monitoring and Implantable Drug Delivery Systems for Diabetes Management.

The global cost of diabetes care exceeds $1 trillion each year with more than $327 billion being spent in the United States alone. Despite some of the advances in diabetes care including continuous glucose monitoring systems and insulin pumps, the technology associated with managing diabetes has largely remained unchanged over the past several decades. With the rise of wearable electronics and novel functional materials, the field is well-poised for the next generation of closed-loop diabetes care. Wearable glucose sensors implanted within diverse platforms including skin or on-tooth tattoos, skin-mounted patches, eyeglasses, contact lenses, fabrics, mouthguards, and pacifiers have enabled noninvasive, unobtrusive, and real-time analysis of glucose excursions in ambulatory care settings. These wearable glucose sensors can be integrated with implantable drug delivery systems, including an insulin pump, glucose responsive insulin release implant, and islets transplantation, to form self-regulating closed-loop systems. This review article encompasses the emerging trends and latest innovations of wearable glucose monitoring and implantable insulin delivery technologies for diabetes management with a focus on their advanced materials and construction. Perspectives on the current unmet challenges of these strategies are also discussed to motivate future technological development toward improved patient care in diabetes management.

In Vitro Mechanical Characterization and Modeling of Subcutaneous Adipose Tissue: A Comprehensive Review.

Mechanical models of adipose tissue are important for various medical applications including cosmetics, injuries, implantable drug delivery systems, plastic surgeries, biomechanical applications such as computational human body models for surgery simulation, and blunt impact trauma prediction. This article presents a comprehensive review of in vivo experimental approaches that aimed to characterize the mechanical properties of adipose tissue, and the resulting constitutive models and model parameters identified. In particular, this study examines the material behavior of adipose tissue, including its nonlinear stress-strain relationship, viscoelasticity, strain hardening and softening, rate-sensitivity, anisotropy, preconditioning, failure behavior, and temperature dependency.

Vitamin D3-loaded electrospun cellulose acetate/polycaprolactone nanofibers: Characterization, in-vitro drug release and cytotoxicity studies

Vitamin D deficiency is now a global health problem; despite several drug delivery systems for carrying vitamin D due to low bioavailability and loss bioactivity. Developing a new drug delivery system to deliver vitamin D3 is a strong incentive in the current study. Hence, an implantable drug delivery system (IDDS) was developed from the electrospun cellulose acetate (CA) and ε-polycaprolactone (PCL) nanofibrous membrane, in which the core of implants consists of vitamin D3-loaded CA nanofiber (CAVD) and enclosed in a thin layer of the PCL membrane (CAVD/PCL). CA nanofibrous mat loaded with vitamin D3 at the concentrations of 6, 12, and 20% (w/w) of vitamin D3 were produced using electrospinning. The smooth and bead-free fibers with diameters ranged from 324 to 428 nm were obtained. The fiber diameters increased with an increase in vitamin D3 content. The controlled drug release profile was observed over 30-days, which fit with the zero-order model (R2 > 0.96) in the first stage. The mechanical properties of IDDS were improved. Young's modulus and tensile strength of CAVD/PCL (dry) were161 ± 14 and 13.07 ± 2.5 MPa, respectively. CA and PCL nanofibers are non-cytotoxic based on the results of the in-vitro cytotoxicity studies. This study can further broaden in-vivo study and provide a reference for developing a new IDDS to carry vitamin D3 in the future.

Cross-linked valerolactone copolymer implants with tailorable biodegradation, loading and in vitro release of paclitaxel

Implantable drug delivery systems, formed from degradable and non-degradable polymers, can offer several advantages over traditional dosage forms for sustained drug delivery. The majority of degradable implant systems developed to date are composed of poly(lactide-co-glycolide) (PLGA). However, PLGA-based systems are not suitable for the delivery of all drugs. Each drug is unique in terms of physico-chemical properties, and polymer-drug compatibility plays a significant role in determining a drug formulation's performance. In this study, two novel cross-linkable δ-valerolactone-based copolymers were synthesized and used to prepare cross-linked disc-shaped implants. The manipulation of the composition of the discs and conditions used during drug loading were found to influence various aspects of the delivery system performance including the degree of swelling, degradation, drug-loading and in vitro release. The polymeric discs resulted in no adverse effects following subcutaneous implantation in naïve rats. These studies support further development of cross-linkable valerolactone matrices as implantable formulations for sustained drug delivery.

Carbon fiber reinforced polymers for implantable medical devices

Carbon fibers reinforced polymers (CFRPs) are prolifically finding applications in the medical field, moving beyond the aerospace and automotive industries. Owing to its high strength-to-weight ratio, lightness and radiolucency, CFRP-based materials are emerging to replace traditional metal-based medical implants. Numerous types of polymers matrices can be incorporated with carbon fiber using various manufacturing methods, creating composites with distinct properties. Thus, prior to biomedical application, comprehensive evaluation of material properties, biocompatibility and safety are of paramount importance. In this study, we systematically evaluated a series of novel CFRPs, aiming at analyzing biocompatibility for future development into medical implants or implantable drug delivery systems. These CFRPs were produced either via Carbon Fiber-Sheet Molding Compound or Fused Deposition Modelling-based additive manufacturing. Unlike conventional methods, both fabrication processes afford high production rates in a time-and cost-effective manner. Importantly, they offer rapid prototyping and customization in view of personalized medical devices. Here, we investigate the physicochemical and surface properties, material mutagenicity or cytotoxicity of 20 CFRPs, inclusive of 2 surface finishes, as well as acute and sub-chronic toxicity in mice and rabbits, respectively. We demonstrate that despite moderate in vitro physicochemical and surface changes over time, most of the CFRPs were non-mutagenic and non-cytotoxic, as well as biocompatible in small animal models. Future work will entail extensive material assessment in the context of orthopedic applications such as evaluating potential for osseointegration, and a chronic toxicity study in a larger animal model, pigs.

In vitro anticancer efficacy of Metformin-loaded PLGA nanofibers towards the post-surgical therapy of lung cancer

Metformin (MET) is an antihyperglycemic agent that has recently entered the spotlight as a promising anti-cancer agent. In this work, Poly (lactic-co-glycolic acid) (PLGA) polymer was applied to fabricate nanofibers (NFs) containing MET through the electrospinning method. The NFs were characterized for morphological features, degradation rate, and drug release profile. Besides, in response to treatment of A549 human lung adenocarcinoma cells with free MET and MET-loaded PLGA NFs, the cytotoxicity, accumulation of intracellular reactive oxygen species (ROS), and expression levels of apoptotic genes were investigated. The bead-free, smooth surface, and randomly-oriented MET-loaded electrospun NFs exhibited a relatively constant rate of degradation over the 24 days and an initial rapid drug release at first days, and a sustained discharge for more than 2-week. MET-loaded PLGA NFs displayed significant cytotoxicity on A549 lung cancer cells than free MET after 48 h. Furthermore, MET-loaded NFs were efficient to enhance the intracellular ROS levels causing apoptosis induction in the cancer cells. According to the gene expression investigations, it was uncovered that MET-loaded NFs induce a significant alteration in the expression levels of Bax and Bcl-2, caspases-3 and -9 than free MET. Overall, the findings showed anti-cancer efficiency of the MET-loaded PLGA nanofibrous scaffold signifying its potential application as an implantable drug delivery system for inhibiting the recurrence of lung cancer after surgical resection.

Evolution of drug-eluting biomedical implants for sustained drug delivery

In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems associated with this type of delivery is that the drug concentration is controlled by first pass metabolism, and therefore may not always remain within the therapeutic window. Implantable drug delivery systems (IDDSs) are an excellent alternative to traditional delivery because they offer the ability to precisely control the drug release, deliver drugs locally to the target tissue, and avoid the toxic side effects often experienced with systemic administration. Since the creation of the first FDA-approved IDDS in 1990, there has been a surge in research devoted to fabricating and testing novel IDDS formulations. The versatility of these systems is evident when looking at the various biomedical applications that utilize IDDSs. This review provides an overview of the history of IDDSs, with examples of the different types of IDDS formulations, as well as looking at current and future biomedical applications for such systems. Though there are still obstacles that need to be overcome, ever-emerging new technologies are making the manufacturing of IDDSs a rewarding therapeutic endeavor with potential for further improvements.

In Vitro Tests of FDM 3D-Printed Diclofenac Sodium-Containing Implants.

One of the most promising emerging innovations in personalized medication is based on 3D printing technology. For use as authorized medications, 3D-printed products require different in vitro tests, including dissolution and biocompatibility investigations. Our objective was to manufacture implantable drug delivery systems using fused deposition modeling, and in vitro tests were performed for the assessment of these products. Polylactic acid, antibacterial polylactic acid, polyethylene terephthalate glycol, and poly(methyl methacrylate) filaments were selected, and samples with 16, 19, or 22 mm diameters and 0%, 5%, 10%, or 15% infill percentages were produced. The dissolution test was performed by a USP dissolution apparatus 1. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide dye (MTT)-based prolonged cytotoxicity test was performed on Caco-2 cells to certify the cytocompatibility properties. The implantable drug delivery systems were characterized by thermogravimetric and heatflow assay, contact angle measurement, scanning electron microscopy, microcomputed tomography, and Raman spectroscopy. Based on our results, it can be stated that the samples are considered nontoxic. The dissolution profiles are influenced by the material properties of the polymers, the diameter, and the infill percentage. Our results confirm the potential of fused deposition modeling (FDM) 3D printing for the manufacturing of different implantable drug delivery systems in personalized medicine and may be applied during surgical interventions.

Development of Porous Polyurethane Implants Manufactured via Hot-Melt Extrusion.

Implantable drug delivery systems (IDDSs) offer good patient compliance and allow the controlled delivery of drugs over prolonged times. However, their application is limited due to the scarce material selection and the limited technological possibilities to achieve extended drug release. Porous structures are an alternative strategy that can overcome these shortcomings. The present work focuses on the development of porous IDDS based on hydrophilic (HPL) and hydrophobic (HPB) polyurethanes and chemical pore formers (PFs) manufactured by hot-melt extrusion. Different PF types and concentrations were investigated to gain a sound understanding in terms of extrudate density, porosity, compressive behavior, pore morphology and liquid uptake. Based on the rheological analyses, a stable extrusion process guaranteed porosities of up to 40% using NaHCO3 as PF. The average pore diameter was between 140 and 600 µm and was indirectly proportional to the concentration of PF. The liquid uptake of HPB was determined by the open pores, while for HPL both open and closed pores influenced the uptake. In summary, through the rational selection of the polymer type, the PF type and concentration, porous carrier systems can be produced continuously via extrusion, whose properties can be adapted to the respective application site.

Modelling of combination therapy using implantable anticancer drug delivery with thermal ablation in solid tumor

Local implantable drug delivery system (IDDS) can be used as an effective adjunctive therapy for solid tumor following thermal ablation for destroying the residual cancer cells and preventing the tumor recurrence. In this paper, we develop comprehensive mathematical pharmacokinetic/pharmacodynamic (PK/PD) models for combination therapy using implantable drug delivery system following thermal ablation inside solid tumors with the help of molecular communication paradigm. In this model, doxorubicin (DOX)-loaded implant (act as a transmitter) is assumed to be inserted inside solid tumor (acts as a channel) after thermal ablation. Using this model, we can predict the extracellular and intracellular concentration of both free and bound drugs. Also, Impact of the anticancer drug on both cancer and normal cells is evaluated using a pharmacodynamic (PD) model that depends on both the spatiotemporal intracellular concentration as well as characteristics of anticancer drug and cells. Accuracy and validity of the proposed drug transport model is verified with published experimental data in the literature. The results show that this combination therapy results in high therapeutic efficacy with negligible toxicity effect on the normal tissue. The proposed model can help in optimize development of this combination treatment for solid tumors, particularly, the design parameters of the implant.

Fabrication and in-vitro experimental study on an implantable controlled drug delivery system with micro-hole for zero-order release

Drug delivery is essential for effective therapy. Implantable controlled drug delivery systems (ICDDS) have become a research focus due to the associated advantages of continuous, long-duration, sustained delivery and the reduced side effects associated with this form of drug release. ICDDS can be designed to release drugs in accordance with different demands. Zero-order drug release, which involves a theoretically linear relationship between the cumulative amount of released drug and the amount of time taken for the release, is an important drug release rule for the control of chronic diseases. However, the release process is influenced by various parameters and zero-order drug release is therefore difficult to achieve. In this study, to achieve zero-order drug release, an implantable controlled drug delivery system with micro-hole (ICDDSM) was designed and fabricated with degradable polymer. Based on micro electromechanical systems (MEMS) technology, ICDDSM matrixes with circular and honeycomb structures were fabricated using the hot-press shaping method at a temperature of 75 °C, 30 N of force which were maintained for 150 s. A micro-hole with a diameter 100 μm was formed using a femto-second laser. 5-fluorouracil was loaded into the ICDDSM and in-vitro experiments were conducted in 37 °C normal saline solution. The experimental results showed that the 20 mg of loaded 5-fluorouracil was released in 720 h with the relationship between the cumulative amount of released drug and the drug release time tending predominantly toward linearity. Zero-order drug release was thus achieved. This study proposed a new degradable ICDDS structure to achieve zero-order drug release, and the hot-press shaping process proved feasible for the efficient fabrication of the lower-cost polymer structure.

Implantable fibrous scaffold with hierarchical microstructure for the ‘on-site’ synergistic cancer therapy

The tissue-targeting delivery and intracellular transportation of therapeutics have been highly demanded for effective cancer therapy, but remains challenging. We hereby report an implantable scaffold consisting of composite fibers with unique particle-on-fiber microstructure for localized synergistic chemo-/starvation therapy. In this system, silica nanoparticles are loaded with glucose oxidase (GOx) and protected by a polydopamine (PDA) coating. A hypoxia-activated prodrug (banoxantrone, AQ4N) is absorbed at the particle surface (MGPA). Meanwhile, biodegradable fibrous scaffold, composed of polycaprolactone (PCL) and gelatin, are incorporated with hyaluronidase (HAase), and self-assembled with MGPA nanoparticles. When the composite scaffold is implanted at the tumor site, particle liberation occurs in a pH-dependent manner. HAase released effectively decomposes extracellular matrix (ECM), and thereby promote the cellular uptake of MGPA nanoparticles. Subsequently, MGPA exhausts intracellular glucose and O2, and in turn activates AQ4N to toxic AQ4. The findings indicate that this scaffold can significantly enhance accumulation of therapeutics at tumor site for a prolonged period and resulted in promoted tumor inhibition. This study has therefore proposed an alternative design of therapeutic device, potentially combining advantages of nanoparticle-form and implantable drug delivery systems, for cancer treatment with high efficacy.

Chinese expert consensus and practice guideline of totally implantable access port for digestive tract carcinomas.

Totally implantable access port is a fully implantable drug delivery system that is implanted subcutaneously and can be retained for a long time. Advantages of ports include a simple nursing process, low risk of infection and embolism, and high patient comfort. In order to promote the standardized application of ports in the treatment of digestive tract tumors and reduce port-related complications, the Chinese Research Hospital Association Digestive Tumor Committee, the Chinese Association of Upper Gastrointestinal Surgeons, the Chinese Gastric Cancer Association, and the Gastrointestinal Surgical Group of Chinese Surgical Society Affiliated to Chinese Medical Association have organized multidisciplinary expert discussions at the General Hospital of the People’s Liberation Army and nation-wide expert letter reviews and on-site seminars, and formulated an expert consensus of the operation guidelines.

Regulation of the Ocular Cell/Tissue Response by Implantable Biomaterials and Drug Delivery Systems.

Therapeutic advancements in the treatment of various ocular diseases is often linked to the development of efficient drug delivery systems (DDSs), which would allow a sustained release while maintaining therapeutic drug levels in the target tissues. In this way, ocular tissue/cell response can be properly modulated and designed in order to produce a therapeutic effect. An ideal ocular DDS should encapsulate and release the appropriate drug concentration to the target tissue (therapeutic but non-toxic level) while preserving drug functionality. Furthermore, a constant release is usually preferred, keeping the initial burst to a minimum. Different materials are used, modified, and combined in order to achieve a sustained drug release in both the anterior and posterior segments of the eye. After giving a picture of the different strategies adopted for ocular drug release, this review article provides an overview of the biomaterials that are used as drug carriers in the eye, including micro- and nanospheres, liposomes, hydrogels, and multi-material implants; the advantages and limitations of these DDSs are discussed in reference to the major ocular applications.