Ambika Bajpayee · Northeastern University · PhdFit
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Dr. Sarah Chen
Stanford · NLP & interpretability
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The Bajpayee Lab works at the intersection of biomaterials design, nanomedicine and translational research. We utilize the body’s internal electric fields to design electrically charged biomaterials using proteins, peptides and cellular materials like exosomes, for targeting difficult to reach tissues for applications in drug delivery and diagnostic imaging. Negatively charged tissues such as cartilage, meniscus, intervertebral disc, eye, and mucosal membrane, that also tend to be dense and avascular, are ubiquitous in the human body but remain outstanding challenges for targeted drug delivery. Their degeneration is associated with several common diseases that remain untreatable due to a lack of delivery systems that can enable drugs to penetrate the negatively charged matrix and reach their cellular targets. The high negative fixed charge density, however, can be converted from being a challenge to an opportunity by engineering therapeutics at the molecular level to add optimally posi
Extracellular vesicles (EVs) are naturally secreted, non-nuclear lipid nanostructures by biological sources with intrinsic features such as biocompatibility, low immunogenicity, and the ability to bypass biological barriers. Despite the growing interest in EV research, their biological potential as a versatile drug delivery vehicle has yet to be widely translated for clinical use. Fewer than 3 % of clinical trials involving these cell-free vesicles have utilized them for drug delivery applications. This review elucidates the reasons behind the translational gap through a comprehensive analysis of pharmacokinetic and tissue transport challenges faced by EVs across various tissue barriers, including the cartilage, blood-brain interface, ocular, gastrointestinal, and skin tissues, and summarizes their endogenous roles within these tissue microenvironments. The review also delves into key engineering design principles, presenting a portfolio of both tissue-specific and tissue-independent targeting strategies to overcome tissue barriers and enhance the precise delivery of engineered EVs. A comprehensive comparison of key factors – such as biodistribution, cellular uptake, intracellular fate, and safety profile – between EVs and benchmark synthetic platforms is also provided to guide the selection of optimal carrier designs for diverse tissue targets and further highlights the steps needed to bridge translational gaps of engineered EVs from a clinical perspective. In conclusion, the review underscores the significance of engineered EVs as a promising next-generation nanocarrier for precision nanomedicine, offering an alternative to conventional synthetic platforms. • Fewer than 3 % of over 600 EV clinical trials focus on delivery vehicles, highlighting limited rational design approaches. • Engineering EVs with tissue-specific or tissue-agnostic ligands enables targeting across diverse biological barriers. • Anionic ECM of tissues offers universal charge-based design cues for EV engineering • EVs achieve ∼20 × higher natural endosomal escape than synthetic lipid nanoparticles, boosting RNA delivery. • Hybrid EV–liposome systems merge EV safety and targeting with improved cargo loading, overcoming EV capacity limits.
Journal of Orthopaedic Research® · 2022-05-17 · 5 citations
articleOpen access
Adolescent obesity has risen dramatically in the last few decades. While adult obesity may be osteoprotective, the effects of obesity during adolescence, which is a period of massive bone accrual, are not clear. We used a murine model of induced adolescent obesity to examine the structural, mechanical, and compositional differences between obese and healthy weight bone in 16-week-old female C57Bl6 mice. We also examined the effects of a return to normal weight after skeletal maturity (24 weeks old). We found obese adolescent bone exhibited decreased trabecular bone volume, increased cortical diameter, increased ultimate stress, and increased brittleness (decreased plastic energy to fracture), similar to an aging phenotype. The trabecular bone deficits remained after return to normal weight after skeletal maturity. However, after returning to normal diet, there was no difference in ultimate stress nor plastic energy to fracture between groups as the normal diet group increased ultimate stress and brittleness. Interestingly, compositional changes appeared in the former high-fat diet mice after skeletal maturity with a lower mineral to matrix ratio compared to normal diet mice. In addition there was a trend toward increased fluorescent advanced glycation endproducts in the former high-fat diet mice compared to normal diet mice but this did not reach significance (p < 0.05) due to the large variability. The skeletal consequences of adolescent obesity may have lasting implications for the adult skeleton even after return to normal weight. Given the rates of adolescent obesity, skeletal health should be a concern.
Journal of Biomechanical Engineering · 2022-11-23 · 6 citations
article
Biphasic poro-viscoelastic constitutive material model (BPVE) captures both the fluid flow dependent and independent behavior of cartilage under stress relaxation type indentation. A finite element model based on BPVE formulation was developed to explore the sensitivity of the model to Young's modulus, Poisson's ratio, permeability, and viscoelastic constitutive parameters expressed in terms of Prony series coefficients. Then we fit the numerical model to experimental force versus time curves from stress relaxation indents on bovine tibial plateaus to extract the material properties. Measurements were made over the period of two days to capture the material property changes that resulted from trypsin-induced degradation. We measured spatial and temporal changes in mechanical properties in the cartilage. The areas of degradation were characterized by an increase in both permeability and summation of Prony series shear relaxation amplitude constants. These findings suggest that cartilage degradation reduces the intrinsic viscoelastic properties of the solid phase of the tissue in addition to impairing its capacity to offer frictional drag to the interstitial fluid flow (permeability). The changes in material properties are measurable well before structural degradation occurs.
Journal of Visualized Experiments · 2020-08-10 · 6 citations
articleSenior author
Several negatively charged tissues in the body, like cartilage, present a barrier to the targeted drug delivery due to their high density of negatively charged aggrecans and, therefore, require improved targeting methods to increase their therapeutic response. Because cartilage has a high negative fixed charge density, drugs can be modified with positively charged drug carriers to take advantage of electrostatic interactions, allowing for enhanced intra-cartilage drug transport. Studying the transport of drug carriers is, therefore, crucial towards predicting the efficacy of drugs in inducing a biological response. We show the design of three experiments which can quantify the equilibrium uptake, depth of penetration and non-equilibrium diffusion rate of cationic peptide carriers in cartilage explants. Equilibrium uptake experiments provide a measure of the solute concentration within the cartilage compared to its surrounding bath, which is useful for predicting the potential of a drug carrier in enhancing therapeutic concentration of drugs in cartilage. Depth of penetration studies using confocal microscopy allow for the visual representation of 1D solute diffusion from the superficial to deep zone of cartilage, which is important for assessing whether solutes reach their matrix and cellular target sites. Non-equilibrium diffusion rate studies using a custom-designed transport chamber enables the measurement of the strength of binding interactions with the tissue matrix by characterizing the diffusion rates of fluorescently labeled solutes across the tissue; this is beneficial for designing carriers of optimal binding strength with cartilage. Together, the results obtained from the three transport experiments provide a guideline for designing optimally charged drug carriers which take advantage of weak and reversible charge interactions for drug delivery applications. These experimental methods can also be applied to evaluate the transport of drugs and drug-drug carrier conjugates. Further, these methods can be adapted for the use in targeting other negatively charged tissues such as meniscus, cornea and the vitreous humor.
