Engineering platforms for localized long-acting immune modulation.

Systemic immunotherapeutics have been a clinical staple in the treatment of cancer, infectious diseases, organ and cell transplantation, autoimmunity, and allergies. Although their utility remains unquestioned, systemic administration of these drugs is associated with limited efficacy, significant adverse off-target effects, transient activity, and the requirement for frequent repeated dosing. To this end, recent technological advancements have provided novel means for sustained drug delivery to specific tissues and targeted localized approaches for immunotherapeutics. In this article, we present various cutting-edge platform technologies, including implants, multireservoir systems, and scaffolds encapsulating immunomodulatory agents for local administration. Examples of their application in cancer, cell transplantation, allergy, and infectious diseases are discussed, highlighting the potential of such systems for innovative immunomodulatory intervention.

3D bioprinted mesenchymal stem cell laden scaffold enhances subcutaneous vascularization for delivery of cell therapy.

Subcutaneous delivery of cell therapy is an appealing minimally-invasive strategy for the treatment of various diseases. However, the subdermal site is poorly vascularized making it inadequate for supporting engraftment, viability, and function of exogenous cells. In this study, we developed a 3D bioprinted scaffold composed of alginate/gelatin (Alg/Gel) embedded with mesenchymal stem cells (MSCs) to enhance vascularization and tissue ingrowth in a subcutaneous microenvironment. We identified bio-ink crosslinking conditions that optimally recapitulated the mechanical properties of subcutaneous tissue. We achieved controlled degradation of the Alg/Gel scaffold synchronous with host tissue ingrowth and remodeling. Further, in a rat model, the Alg/Gel scaffold was superior to MSC-embedded Pluronic hydrogel in supporting tissue development and vascularization of a subcutaneous site. While the scaffold alone promoted vascular tissue formation, the inclusion of MSCs in the bio-ink further enhanced angiogenesis. Our findings highlight the use of simple cell-laden degradable bioprinted structures to generate a supportive microenvironment for cell delivery.

Prophylactic and therapeutic cancer vaccine with continuous localized immunomodulation.

Selective in vivo immune cell manipulation offers a promising strategy for cancer vaccines. In this context, spatiotemporal control over recruitment of specific cells, and their direct exposure to appropriate immunoadjuvants and antigens are key to effective cancer vaccines. We present an implantable 3D-printed cancer vaccine platform called the 'NanoLymph' that enables spatiotemporally-controlled recruitment and manipulation of immune cells in a subcutaneous site. Leveraging two reservoirs each for continuous immunoadjuvant release or antigen presentation, the NanoLymph attracts dendritic cells (DCs) on site and exposes them to tumor-associated antigens. Upon local antigen-specific activation, DCs are mobilized to initiate a systemic immune response. NanoLymph releasing granulocyte-macrophage colony-stimulating factor and CpG-oligodeoxynucleotides with irradiated whole cell tumor lysate inhibited tumor growth of B16F10 murine melanoma in a prophylactic and therapeutic vaccine setting. Overall, this study presents the NanoLymph as a versatile cancer vaccine development platform with replenishable and controlled local release of antigens and immunoadjuvants.

Zonal Intratumoral Delivery of Nanoparticles Guided by Surface Functionalization.

Delivery of small molecules and anticancer agents to malignant cells or specific regions within a tumor is limited by penetration depth and poor spatial drug distribution, hindering anticancer efficacy. Herein, we demonstrate control over gold nanoparticle (GNP) penetration and spatial distribution across solid tumors by administering GNPs with different surface chemistries at a constant injection rate via syringe pump. A key finding in this study is the discovery of different zone-specific accumulation patterns of intratumorally injected nanoparticles dependent on surface functionalization. Computed tomography (CT) imaging performed in vivo of C57BL/6 mice harboring Lewis lung carcinoma (LLC) tumors on their flank and gross visualization of excised tumors consistently revealed that intratumorally administered citrate-GNPs accumulate in particle clusters in central areas of the tumor, while GNPs functionalized with thiolated phosphothioethanol (PTE-GNPs) and thiolated polyethylene glycol (PEG-GNPs) regularly accumulate in the tumor periphery. Further, PEG functionalization resulted in larger tumoral surface coverage than PTE, reaching beyond the outer zone of the tumor mass and into the surrounding stroma. To understand the dissimilarities in spatiotemporal evolution across the different GNP surface chemistries, we modeled their intratumoral transport with reaction-diffusion equations. Our results suggest that GNP surface passivation affects nanoparticle reactivity with the tumor microenvironment, leading to differential transport behavior across tumor zones. The present study provides a mechanistic understanding of the factors affecting spatiotemporal distribution of nanoparticles in the tumor. Our proof of concept of zonal delivery within the tumor may prove useful for directing anticancer therapies to regions of biomarker overexpression.

Long-acting tunable release of amlodipine loaded PEG-PCL micelles for tailored treatment of chronic hypertension.

Hypertension is a chronic condition that requires lifelong therapeutic management. Strict adherence to drug administration timing improves efficacy, while poor adherence leads to safety concerns. In light of these challenges, we present a nanofluidic technology that enables long-acting drug delivery with tunable timing of drug administration using buried gate electrodes in nanochannels. We developed a poly(ethylene glycol) methyl ether-block-poly(ε-caprolactone) (PEG-PCL)-based micellar formulation of amlodipine besylate, a calcium channel blocker for hypertension treatment. The electrostatically charged PEG-PCL micellar formulation enhanced drug solubility and rendered amlodipine responsive to electrostatic release gating in nanochannels for sustained release at clinically relevant therapeutic dose. Using a low-power (<3 VDC) gating potential, we demonstrated tunable release of amlodipine-loaded micelles. Additionally, we showed that the released drug maintained biological activity via calcium ion blockade in vitro. This study represents a proof of concept for the potential applicability of our strategy for chronotherapeutic management of hypertension.

Advanced implantable drug delivery technologies: transforming the clinical landscape of therapeutics for chronic diseases.

Chronic diseases account for the majority of all deaths worldwide, and their prevalence is expected to escalate in the next 10 years. Because chronic disorders require long-term therapy, the healthcare system must address the needs of an increasing number of patients. The use of new drug administration routes, specifically implantable drug delivery devices, has the potential to reduce treatment-monitoring clinical visits and follow-ups with healthcare providers. Also, implantable drug delivery devices can be designed to maintain drug concentrations in the therapeutic window to achieve controlled, continuous release of therapeutics over extended periods, eliminating the risk of patient non-compliance to oral treatment. A higher local drug concentration can be achieved if the device is implanted in the affected tissue, reducing systemic adverse side effects and decreasing the challenges and discomfort of parenteral treatment. Although implantable drug delivery devices have existed for some time, interest in their therapeutic potential is growing, with a global market expected to reach over $12 billion USD by 2018. This review discusses implantable drug delivery technologies in an advanced stage of development or in clinical use and focuses on the state-of-the-art of reservoir-based implants including pumps, electromechanical systems, and polymers, sites of implantation and side effects, and deployment in developing countries.

Nanofluidic microsystem for sustained intraocular delivery of therapeutics.

Globally, 145.2 million people suffer from moderate to severe vision impairment or blindness due to preventable or treatable causes. However, patient adherence to topical or intravitreal treatment is a leading cause of poor outcomes. To address this issue, we designed an intraocularly implantable device called the nanofluidic Vitreal System for Therapeutic Administration (nViSTA) for continuous and controlled drug release based on a nanochannel membrane that obviates the need for pumps or actuation. In vitro release analysis demonstrated that our device achieves sustained release of bimatoprost (BIM) and dexamethasone (DEX) at concentrations within clinically relevant therapeutic window. In this proof of concept study, we constructed an anatomically similar in silico human eye model to simulate DEX release from our implant and gain insight into intraocular pharmacokinetics profile. Overall, our drug-agnostic intraocular implant represents a potentially viable platform for long-term treatment of various chronic ophthalmologic diseases, including diabetic macular edema and uveitis.

Efficacy of sustained delivery of GC-1 from a Nanofluidic system in a spontaneously obese non-human primate: a case study.

With nearly 40% of U.S. adults obese, and childhood and adolescent rates rising, obesity and associated comorbidities are serious public health concerns with massive societal costs. Often, lifestyle interventions do not offer sufficient weight loss to improve health, requiring surgery and medications as adjunct management strategies. Here, we present a 4-month case study in which the sustained, low-dose, and constant administration of the thyroid receptor ß selective agonist GC-1 (sobetirome) from a novel nanochannel membrane implant was assessed in an obese, pre-diabetic rhesus macaque. Dramatic loss of white adipose tissue in the abdomen from 36 to 18% was observed via magnetic resonance imaging in conjunction with normalized serum insulin and glycemia, with no signs of cardiotoxicity shown. The non-human primate study highlights sustained low-dose delivery of GC-1 from our minimally invasive subcutaneous implant as a valuable approach to induce weight loss and manage obesity and comorbidities, including type 2 diabetes.

Remote magnetic switch off microgate for nanofluidic drug delivery implants.

In numerous pathologies, implantable drug delivery devices provide advantages over conventional oral or parenteral approaches. Based on the site of implantation and release characteristics, implants can afford either systemic delivery or local administration, whereby the drug is delivered at or near the site of intended action. Unfortunately, current implantable drug delivery systems provide limited options for intervention in the case of an adverse reaction to the drug or the need for dosage adjustment. In the event that drug delivery must be terminated, an urgent surgical retrieval may be the only reliable option. This could be a time sensitive and costly effort, requiring access to trained professionals and emergency medical facilities. To address such limitations, here we demonstrate, in vitro and ex vivo, a novel microsystem for the rapid and effective switch off of drug delivery from an implantable nanofluidic system, by applying a safe external electromagnetic field in the FDA approved dose range. This study represents a proof of concept for a technology with potential for broad applicability to reservoir-based delivery implants for both complete interruption or remote titration of drug administration.

A pharmacokinetic study of GC-1 delivery using a nanochannel membrane device.

This study demonstrated a nanochannel membrane device (NMD) for controlled and sustained release of GC-1 in rats, in the context of the treatment of metabolic syndrome. Release profiles were established in vitro both with and without 5% labrasol for over 2 months. In vivo pharmacokinetic evaluation showed effective GC-1 plasma concentrations, which resulted in significant reductions in body weight after just one week of treatment when compared to the NMD releasing vehicle only (PBS). We also provided evidence that rats treated with NMD-GC-1 present sub-active thyroids and clear differences in the morphology of the epithelium and follicles as compared to the controls, while the heart showed changes in weight. Moreover, body temperatures remained stable throughout treatment, and glucose, pancreatic islet size, and liver histology appeared similar between the treated and control groups. Prolonged constant administration of GC-1 from the NMD proved to be a valid strategy to facilitate weight loss.

Impedance characterization, degradation, and in vitro biocompatibility for platinum electrodes on BioMEMS.

Fine control of molecular transport through microfluidic systems can be obtained by modulation of an applied electrical field across channels with the use of electrodes. In BioMEMS designed for biological fluids and in vivo applications, electrodes must be biocompatible, biorobust and stable. In this work, the analysis and characterization of platinum (Pt) electrodes integrated on silicon substrates for biomedical applications are presented. Electrodes were incorporated on the surface of silicon chips by adhesion of laminated Pt foils or deposited at 30°, 45° or 90° angle by e-beam or physical vapor (sputtering) methods. Electrical and physical properties of the electrodes were quantified and evaluated using electrical impedance spectroscopy and modelling of the electrode-electrolyte interfaces. Electrode degradation in saline solution at pH 7.4 was tested at room temperature and under accelerated conditions (90 °C), both in the presence and absence of an applied electrical potential. Degradation was quantified using atomic force microscopy (AFM) and inductively coupled plasma mass spectroscopy (ICP-MS). Biocompatibility was assessed by MTT proliferation assay with human dermal fibroblasts. Results demonstrated that the deposited electrodes were biocompatible with negligible material degradation and exhibited electrochemical behavior similar to Pt foils, especially for e-beam deposited electrodes. Finally, Pt electrodes e-beam deposited on silicon nanofabricated nanochannel membranes were evaluated for controlled drug delivery applications. By tuning a low applied electrical potential (<1.5 VDC) to the electrodes, temporal modulation of the dendritic fullerene 1 (DF-1) release from a source reservoir was successfully achieved as a proof of concept, highlighting the potential of deposited electrodes in biomedical applications.

The nanochannel delivery system for constant testosterone replacement therapy.

INTRODUCTION: The goal of testosterone replacement is to provide long-term physiological supplementation at sufficient levels to mitigate the symptoms of hypogonadism. AIM: The objective of this work is to determine if the implantable nanochannel delivery system (nDS) can present an alternative delivery strategy for the long-term sustained and constant release of testosterone. METHODS: A formulation of common testosterone esters (F1) was developed to enable nanochannel delivery of the low water soluble hormone. In vivo evaluation of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels by liquid chromatography/mass spectrometry and a multiplex assay, respectively, in castrated Sprague-Dawley rats implanted with nDS-F1 implants or polymeric pellets was performed over a 6-month period. The percent of testosterone concentrations observed that fell within the normal range of testosterone levels for each animal was calculated and used to compare the study groups. MAIN OUTCOME MEASURES: Sustain release of testosterone in vivo for over 6 months. RESULTS: The subcutaneous release of F1 from nDS implants exhibited sustained in vivo release kinetics and attained stable clinically relevant plasma testosterone levels. Plasma LH and FSH levels were significantly diminished in nDS-F1 implant-treated animals, confirming biological activity of the released testosterone. CONCLUSIONS: In conclusion, we demonstrate that nDS-F1 implants represents a novel approach for the treatment of male hypogonadism. Further studies will be performed in view of translating the technology to clinical use.

Advances in Skin-on-a-Chip Technologies for Dermatological Disease Modeling.

Skin-on-a-chip (SoC) technologies are emerging as a paradigm shift in dermatology research by replicating human physiology in a dynamic manner not achievable by current animal models. Although animal models have contributed to successful clinical trials, their ability to predict human outcomes remains questionable, owing to inherent differences in skin anatomy and immune response. Covering areas including infectious diseases, autoimmune skin conditions, wound healing, drug toxicity, aging, and antiaging, SoC aims to circumvent the inherent disparities created by traditional models. In this paper, we review current SoC technologies, highlighting their potential as an alternative to animal models for a deeper understanding of complex skin conditions.

Modeling of a Bioengineered Immunomodulating Microenvironment for Cell Therapy.

Cell delivery and encapsulation platforms are under development for the treatment of Type 1 Diabetes among other diseases. For effective cell engraftment, these platforms require establishing an immune-protected microenvironment as well as adequate vascularization and oxygen supply to meet the metabolic demands of the therapeutic cells. Current platforms rely on 1) immune isolating barriers and indirect vascularization or 2) direct vascularization with local or systemic delivery of immune modulatory molecules. Supported by experimental data, here a broadly applicable predictive computational model capable of recapitulating both encapsulation strategies is developed. The model is employed to comparatively study the oxygen concentration at different levels of vascularization, transplanted cell density, and spatial distribution, as well as with codelivered adjuvant cells. The model is then validated to be predictive of experimental results of oxygen pressure and local and systemic drug biodistribution in a direct vascularization device with local immunosuppressant delivery. The model highlights that dense vascularization can minimize cell hypoxia while allowing for high cell loading density. In contrast, lower levels of vascularization allow for better drug localization reducing systemic dissemination. Overall, it is shown that this model can serve as a valuable tool for the development and optimization of platform technologies for cell encapsulation.

Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques.

Treatment nonadherence is a pressing issue in people living with HIV (PLWH), as they require lifelong therapy to maintain viral suppression. Poor adherence leads to antiretroviral (ARV) resistance, transmission to others, AIDS progression, and increased morbidity and mortality. Long-acting (LA) ARV therapy is a promising strategy to combat the clinical drawback of user-dependent dosing. Islatravir (ISL) is a promising candidate for HIV treatment given its long half-life and high potency. Here we show constant ISL release from a subdermal LA nanofluidic implant achieves viral load reduction in SHIV-infected macaques. Specifically, a mean delivery dosage of 0.21 ± 0.07 mg/kg/day yielded a mean viral load reduction of -2.30 ± 0.53 log10 copies/mL at week 2, compared to baseline. The antiviral potency of the ISL delivered from the nanofluidic implant was higher than oral ISL dosed either daily or weekly. At week 3, viral resistance to ISL emerged in 2 out of 8 macaques, attributable to M184V mutation, supporting the need of combining ISL with other ARV for HIV treatment. The ISL implant produced moderate reactivity in the surrounding tissue, indicating tolerability. Overall, we present the ISL subdermal implant as a promising approach for LA ARV treatment in PLWH.

Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead.

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic ß cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable ß cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment.

Characterization of nanochannel delivery membrane systems for the sustained release of resveratrol and atorvastatin: new perspectives on promoting heart health.

Novel drug delivery systems capable of continuous sustained release of therapeutics have been studied extensively for use in the prevention and management of chronic diseases. The use of these systems holds promise as a means to achieve higher patient compliance while improving therapeutic index and reducing systemic toxicity. In this work, an implantable nanochannel drug delivery system (nDS) is characterized and evaluated for the long-term sustained release of atorvastatin (ATS) and trans-resveratrol (t-RES), compounds with a proven role in managing atherogenic dyslipidemia and promoting cardioprotection. The primary mediators of drug release in the nDS are nanofluidic membranes with hundreds of thousands of nanochannels (up to 100,000/mm(2)) that attain zero-order release kinetics by exploiting nanoconfinement and molecule-to-surface interactions that dominate diffusive transport at the nanoscale. These membranes were characterized using gas flow analysis, acetone diffusion, and scanning and transmission electron microscopy (SEM, TEM). The surface properties of the dielectric materials lining the nanochannels, SiO(2) and low-stress silicon nitride, were further investigated using surface charge analysis. Continuous, sustained in vitro release for both ATS and t-RES was established for durations exceeding 1 month. Finally, the influence of the membranes on cell viability was assessed using human microvascular endothelial cells. Morphology changes and adhesion to the surface were analyzed using SEM, while an MTT proliferation assay was used to determine the cell viability. The nanochannel delivery approach, here demonstrated in vitro, not only possesses all requirements for large-scale high-yield industrial fabrication, but also presents the key components for a rapid clinical translation as an implantable delivery system for the sustained administration of cardioprotectants.

Robotic self-modulation enhances implantable long-acting drug delivery devices.

Integrating fibrotic capsule sensing with soft robotics may boost long-term performance of implantable drug delivery devices.