Antiretroviral (ARV) Properties Dictate Long-Acting Release and Tissue Partitioning Behaviors in Multidrug Subcutaneous Implants.

Subcutaneous implants can provide patients with long-acting, compliance-independent drug dosing. For this reason, subcutaneous implants have shown emerging interest in human immunodeficiency virus (HIV) prevention. However, any successful long-acting HIV-prevention device will require multidrug dosing, which poses a challenge for formulation considering the physicochemically diverse selection of antiretroviral (ARV) candidates. As a method that has shown the capacity of efficient multidrug delivery, we assessed electrospun fiber implants composed of three synergistically potent ARVs and a biodegradable polymer selected by in vitro release studies. In mice, subcutaneous electrospun fiber implants exhibit burst release of the more hydrophilic drugs maraviroc (MVC) and raltegravir (RAL), which could be reduced via simple prewash treatments of the implants. Over an extended 120 day time frame, fiber implants show drug-specific differences in release time frames and magnitudes in blood serum. However, end-point drug tissue concentrations show that the most hydrophobic drug etravirine (ETR) remains in high concentrations within the implant and in local skin tissue biopsies. Furthermore, ETR is found to be capable of significant partitioning into lymph nodes, the lower female reproductive tract, and the rectum. Topologically smooth film implants also exhibit the same drug-dependent trends. Therefore, we illustrate that drug release and drug tissue partitioning are largely dictated by drug properties. Further, we find that the properties of ETR enable significant drug quantities within the tissues most relevant to HIV protection. Evidence from this work emphasizes the need for a greater focus on drug properties and prodrug strategies to enable relevant, extended, and targeted drug release.

Fostering Community and Inclusion in a Team-Based Hybrid Bioengineering Lab Course.

As cornerstones of biomedical engineering and bioengineering undergraduate programs, hands-on laboratory experiences promote key skill development and student engagement. Lab courses often involve team-based activities and close communication with instructors, allowing students to build connection and community. Necessitated by the pandemic, changes to class delivery format presented unprecedented challenges to student inclusion and engagement, especially for students from underrepresented minority backgrounds. Here, we present a multi-faceted approach for fostering inclusion and community-building in a hybrid bioengineering laboratory course. A basis for this project was an approach for team-based project work which allowed students to have hands-on experience in the lab and collaborate extensively with peers, while abiding by social distancing guidelines. Members of each student team worked together remotely and synchronously on a project. One team member executed the hands-on portion of each lab activity and the remote student(s) engaged in the project via online communication. The hybrid lab course was supplemented with interventions to further promote inclusivity and community, including instructor modeling on inclusion, team-based course content, attention to lab session logistics, and instructor communication. Students responded positively, as indicated by the median ratings in course evaluations for the four lab sections in the following categories concerning course climate (using a 5.0 scale): their overall comfort with the climate of the course (4.8 to 5.0), feeling valued and respected by lab instructor (4.8 to 5.0) and their peers (4.8 to 5.0), peers helping each other succeed in the course (4.5 to 5.0), and the degree to which the experience in the course contributed to their sense of belonging in engineering (4.2 to 5.0). When asked to describe aspects of the class that contributed to inclusivity towards differences, students cited a collaborative environment, course content on implicit bias and inclusivity, and an approachable teaching team. Overall, our approach was effective in fostering a sense of community and inclusion. We anticipate many of these initiatives can transcend instructional format to positively impact future lab course offerings, irrespective of modality. Supplementary Information: The online version contains supplementary material available at 10.1007/s43683-022-00081-4.

Medical Applications of Porous Biomaterials: Features of Porosity and Tissue-Specific Implications for Biocompatibility.

Porosity is an important material feature commonly employed in implants and tissue scaffolds. The presence of material voids permits the infiltration of cells, mechanical compliance, and outward diffusion of pharmaceutical agents. Various studies have confirmed that porosity indeed promotes favorable tissue responses, including minimal fibrous encapsulation during the foreign body reaction (FBR). However, increased biofilm formation and calcification is also described to arise due to biomaterial porosity. Additionally, the relevance of host responses like the FBR, infection, calcification, and thrombosis are dependent on tissue location and specific tissue microenvironment. In this review, the features of porous materials and the implications of porosity in the context of medical devices is discussed. Common methods to create porous materials are also discussed, as well as the parameters that are used to tune pore features. Responses toward porous biomaterials are also reviewed, including the various stages of the FBR, hemocompatibility, biofilm formation, and calcification. Finally, these host responses are considered in tissue specific locations including the subcutis, bone, cardiovascular system, brain, eye, and female reproductive tract. The effects of porosity across the various tissues of the body is highlighted and the need to consider the tissue context when engineering biomaterials is emphasized.

Characterization of Immune Cells in Oral Tissues of Non-human Primates.

The oral mucosa contains distinct tissue sites with immune niches capable of either immunogenic or tolerogenic responses. However, immune cell compositions within oral mucosal tissues at homeostasis have not been well-characterized in human relevant tissues. Non-human primates (NHP) are a major model for the human immune system and oral anatomy, and therefore improved understanding of NHP oral immune cell populations can provide important insights for studying disease pathologies and developing therapies. Herein, we characterize immune cell types of three sites within the oral cavity (buccal, sublingual, lingual tonsil) sampled by biopsy and cytobrush in pigtail macaques. Tonsil biopsies had more T-cells, dendritic cells (DCs), DC subtypes, and CD4+ T-cells than buccal or sublingual biopsies when normalized by tissue mass. Biopsy proved to collect more immune cells than cytobrushes, however frequencies of CD45+ subpopulations were comparable between methods. Live cells isolated from biopsied tonsils had greater CD45+ leukocyte frequencies (mean 31.6 ± SD 20.4%) than buccal (13.8 ± 4.6%) or sublingual (10.0 ± 5.1%) tissues. T-cells composed more than half of the CD45+ population in sublingual tissue (60.1 ± 9.6%) and the tonsil (54.6 ± 7.5%), but only 31.9 ± 7.2% in buccal samples. CD20+ B-cells composed a greater percentage of CD45+ leukocytes in the tonsil (12.8 ± 9.1%) than buccal (1.2 ± 1.0%) or sublingual tissues (0.8 ± 1.2%). Immune population comparisons are also made between sex and age. These results present an important step for understanding the oral immune environment, oral disease, and site-specific therapy development.

Effect of tissue microenvironment on fibrous capsule formation to biomaterial-coated implants.

Within tissue exposed to the systemic immune system, lymphocytes and fibroblasts act against biomaterials via the development of a fibrous capsule, known as the foreign body reaction (FBR). Inspired by the natural tolerance that the uterine cavity has to foreign bodies, our study explores the role of microenvironment across classical (subcutaneous) and immune privileged (uterine) tissues in the development of the FBR. As a model biomaterial, we used electrospun fibers loaded with sclerosing agents to provoke scar tissue growth. Additionally, we integrated these materials onto an intrauterine device as a platform for intrauterine biomaterial studies. Polyester materials in vitro achieved drug release up to 10 days, greater pro-inflammatory and pro-healing cytokine expression, and the addition of gelatin enabled greater fibroblast attachment. We observed the materials that induced the greatest FBR in the mouse, had no effect when inserted at the utero-tubal junction of non-human primates. These results suggest that the FBR varies across different tissue microenvironments, and a dampened fibrotic response exists in the uterine cavity, possibly due to immune privilege. Further study of immune privileged tissue factors on biomaterials could broaden our understanding of the FBR and inform new methods for achieving biocompatibility in vivo.