The effect of the foreign body response on drug elution from subdermal delivery systems.

Contrasting findings are presented in the literature regarding the influence of foreign body response (FBR) on drug release from implantable drug delivery systems. To this end, here we sought direct evidence of the effect of the fibrotic tissue on subcutaneous drug release from long-acting drug delivery implants. Specifically, we investigated the pharmacokinetic impact of fibrotic encapsulation on a small molecule drug, islatravir (293 Da), and a large protein, IgG (150 kDa), administered via biocompatible implants.

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 β cells, leading to a disruption in glucose homeostasis.

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.

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.

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.

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.

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.

Intratumoral nanofluidic system enhanced tumor biodistribution of PD-L1 antibody in triple-negative breast cancer.

Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment-refractory triple-negative breast cancer (TNBC), where those with Programmed death-ligand 1 (PD-L1) positive early-stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off-tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach.

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.

Long-acting refillable nanofluidic implant confers protection against SHIV infection in nonhuman primates.

The impact of pre-exposure prophylaxis (PrEP) on slowing the global HIV epidemic hinges on effective drugs and delivery platforms. Oral drug regimens are the pillar of HIV PrEP, but variable adherence has spurred development of long-acting delivery systems with the aim of increasing PrEP access, uptake, and persistence. We have developed a long-acting subcutaneous nanofluidic implant that can be refilled transcutaneously for sustained release of the HIV drug islatravir, a nucleoside reverse transcriptase translocation inhibitor that is used for HIV PrEP.

Changes in local tissue microenvironment in response to subcutaneous long-acting delivery of tenofovir alafenamide in rats and non-human primates.

Several implantable long-acting (LA) delivery systems have been developed for sustained subcutaneous administration of tenofovir alafenamide (TAF), a potent and effective nucleotide reverse transcriptase inhibitor used for HIV pre-exposure prophylaxis (PrEP). LA platforms aim to address the lack of adherence to oral regimens, which has impaired PrEP efficacy. Despite extensive investigations in this field, tissue response to sustained subcutaneous TAF delivery remains to be elucidated as contrasting preclinical results have been reported in the literature.

Sustained Intratumoral Administration of Agonist CD40 Antibody Overcomes Immunosuppressive Tumor Microenvironment in Pancreatic Cancer.

Agonist CD40 monoclonal antibodies (mAb) is a promising immunotherapeutic agent for cold-to-hot tumor immune microenvironment (TIME) conversion. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer known as an immune desert, and therefore urgently needs more effective treatment. Conventional systemic treatment fails to effectively penetrate the characteristic dense tumor stroma.

Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats.

Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model.

Emerging immunomodulatory strategies for cell therapeutics.

Cellular therapies are poised to transform the field of medicine by restoring dysfunctional tissues and treating various diseases in a dynamic manner not achievable by conventional pharmaceutics. Spanning various therapeutic areas inclusive of cancer, regenerative medicine, and immune disorders, cellular therapies comprise stem or non-stem cells derived from various sources. Despite numerous clinical approvals or trials underway, the host immune response presents a critical impediment to the widespread adoption and success of cellular therapies.

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.

Advanced strategies to thwart foreign body response to implantable devices.

Mitigating the foreign body response (FBR) to implantable medical devices (IMDs) is critical for successful long-term clinical deployment. The FBR is an inevitable immunological reaction to IMDs, resulting in inflammation and subsequent fibrotic encapsulation. Excessive fibrosis may impair IMDs function, eventually necessitating retrieval or replacement for continued therapy.

Localization of drug biodistribution in a 3D-bioengineered subcutaneous neovascularized microenvironment.

Local immunomodulation has shown the potential to control the immune response in a site-specific manner for wound healing, cancer, allergy, and cell transplantation, thus abrogating adverse effects associated with systemic administration of immunotherapeutics. Localized immunomodulation requires confining the biodistribution of immunotherapeutics on-site for maximal immune control and minimal systemic drug exposure. To this end, we developed a 3D-printed subcutaneous implant termed 'NICHE', consisting of a bioengineered vascularized microenvironment enabled by sustained drug delivery on-site.

Comprehensive Analysis of Electrostatic Gating in Nanofluidic Systems.

Molecular transport in nanofluidic systems exhibits properties that are unique to the nanoscale. Here, the electrostatic and steric interactions between particle and surfaces become dominant in determining particle transport. At the solid-liquid interface of charged surfaces an electric double layer (EDL) forms due to electrostatic interactions between surfaces and charged particles.

Extending drug release from implants via transcutaneous refilling with solid therapeutics.

Long-acting (LA) implantable drug delivery systems (IDDS) offer an effective approach for the management or prevention of chronic conditions by sustained parenteral therapeutic administration. LA IDDS can and improve adherence to treatment regimens by minimizing dosing frequency. However, their clinical deployment is challenged by factors such as poor drug loading capacity, which limit their lifespan and require repeated surgical replacement for continued therapy.

Emerging local immunomodulatory strategies to circumvent systemic immunosuppression in cell transplantation.

Introduction: Cell transplantation is a promising curative therapeutic strategy whereby impaired organ function can be restored without the need for whole-organ transplantation. A key challenge in allotransplantation is the requirement for life-long systemic immunosuppression to prevent rejection, which is associated with serious adverse effects such as increased risk of opportunistic infections and the development of neoplasms. This challenge underscores the urgent need for novel strategies to prevent graft rejection while abrogating toxicity-associated adverse events.

Engineered implantable vaccine platform for continuous antigen-specific immunomodulation.

Cancer vaccines harness the host immune system to generate antigen-specific antitumor immunity for long-term tumor elimination with durable immunomodulation. Commonly investigated strategies reintroduce ex vivo autologous dendritic cells (DCs) but have limited clinical adoption due to difficulty in manufacturing, delivery and low clinical efficacy. To combat this, we designed the "NanoLymph", an implantable subcutaneous device for antigen-specific antitumor immunomodulation.

Emerging biomaterial-based strategies for personalized therapeutic in situ cancer vaccines.

Landmark successes in oncoimmunology have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor reduction in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunologically cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells.

Emerging strategies for beta cell transplantation to treat diabetes.

Beta cell replacement has emerged as an attractive therapeutic alternative to traditional exogenous insulin administration for management of type 1 diabetes (T1D). Beta cells deliver insulin dynamically based on individual glycometabolic requirements, providing glycemic control while significantly reducing patient burden. Although transplantation into the portal circulation is clinically available, poor engraftment, low cell survival, and immune rejection have sparked investigation of alternative strategies for beta cell transplantation.