Biology subjects

Vijayavenkataraman, S.

Publications and source records attributed to Vijayavenkataraman, S..

4 recordsLinked to original sources

bioRxiv2026

A Universal Free-Degree Orientation Extrusion Head Enables Conformal and Non-Planar Bio-Additive Manufacturing toward Adaptive and Future-Ready Bioprinting

Conventional extrusion-based 3D bioprinting encounters limitations in fabricating intricate tissue architectures due to fixed nozzle diameters and fixed deposition orientations. These constraints restrict conformal printing on curved or non-planar surfaces and often necessitate support-intensive fabrication strategies. This work introduces a mechanically simplified extrusion platform inspired by the swivel jet nozzle, featuring a free-degree-of-orientation extrusion head termed the universal extrusion head (Univ-Ex head), coupled with a modular nozzle architecture. The Univ-Ex head employs a swivel-like mechanical design that enables orientation freedom without external actuation in its current implementation, thereby minimizing mechanical complexity while supporting deposition on physiologically relevant, non-planar geometries. Multiple nozzle concepts were developed through comparative CAD iterations, with two representative geometries--a flat nozzle and a conical nozzle--selected for experimental validation. The platform is evaluated through parametric CAD design, stereolithography-printed prototypes, proof-of-concept extrusion experiments, and fluid dynamics simulations performed using FLOW-3D software. Numerical and experimental results demonstrate stable filament formation and clear diameter-dependent extrusion behavior, while simulations further confirm the feasibility of angled and non-planar deposition. A variable-diameter nozzle concept is proposed as a forward design direction to enable real-time adjustment of bioink flow rate and deposition resolution in principle; however, the present study intentionally validates the system using fixed-diameter nozzle variants to maintain stable numerical and experimental boundary conditions. A gear-integrated Univ-Ex head is also presented as a forward upgrade and demonstrated as a single-piece prototype. Collectively, this work establishes a scalable, hardware-focused pathway toward conformal bio-additive manufacturing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/734010v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@7a3213org.highwire.dtl.DTLVardef@6d9748org.highwire.dtl.DTLVardef@e733aforg.highwire.dtl.DTLVardef@f24a86_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Systematic Engineering of Intra-Articular Drug Release Profiles Reveals a Key Determinant of Disease-Modifying Efficacy in Post-Traumatic Osteoarthritis

Post-traumatic osteoarthritis (PTOA) is a progressive joint disease for which no disease-modifying osteoarthritis drugs (DMOADs) have been approved. Although injectable drug delivery systems can prolong therapeutic retention within the joint, it remains unclear whether local drug release kinetics influence disease-modifying efficacy. Here, we developed a modular platform of injectable supramolecular hydrogels using biocompatible, generally recognized as safe (GRAS) amphiphilic molecules and systematically engineered a range of degradation and drug release profiles. Using the cathepsin-K inhibitor L-006235 as a model DMOAD, we generated hydrogels with distinct release kinetics and evaluated their therapeutic performance in PTOA. Hydrogels exhibiting slower degradation and more sustained drug release like Sucrose Stearate (SS hydrogel) showed prolonged intra-articular retention and improved therapeutic outcomes. In a destabilization of the medial meniscus (DMM) mouse model, sustained-release formulations significantly reduced cartilage degeneration, preserved aggrecan expression, improved joint histopathology, and enabled effective monthly dosing. In contrast, formulations with faster degradation and release kinetics required more frequent administration to achieve comparable benefits. To our knowledge, this is the first study to establish local drug release kinetics as a critical determinant of disease-modifying efficacy in PTOA. This work provides one of the clearest demonstrations to date that engineering intra-articular release kinetics, rather than merely prolonging residence time, can improve disease-modifying outcomes. Our findings establish local release kinetics as a key design parameter for osteoarthritis therapeutics and highlight the potential of tunable supramolecular hydrogels for long-acting drug delivery.

bioengineering↗

bioRxiv2026

Softer substrates mechanical primes sustained and metabolically fit CD8+ T cells for anti-tumor activity

Adoptive T cell therapy for solid tumors is limited by poor persistence of CD8+ T cells, a dysfunction that is often programmed during ex vivo expansion. Here, we show that, when biochemical inputs are held constant,substrate mechanics alone can direct durable anti-tumor function in primary human CD8+ T cells. Using polyacrylamide (PA) hydrogels of defined stiffness (soft [~]1 kPa; stiff [~]55 kPa) in both flat and bead formats, we first establish that contact geometry dominates early activation, whereas substrate stiffness governs the 14-day expansion trajectory. Across the rapid expansion protocol, flat PA substrates sustain proliferation, limit PD-1/LAG-3 acquisition, and preserve a balanced effector-regulatory cytokine profile. In contrast, Dynabeads-expanded cells exhibit net cell loss and a more pronounced decline in cytokine output over time. To define the underlying programs, RNA-seq identifies a 125-gene biomimetic core shared by both PA conditions but absent from Dynabeads, encompassing proliferation, OXPHOS, mechanobiology, and a stem-like precursor (Tpex) signature. Consistent with these transcriptional differences, metabolic profiling shows that flat soft PA best preserves dual glycolytic and mitochondrial capacity at day 14, indicating enhanced bioenergetic flexibility. Functionally, PA-primed CD8+ T cells display superior cytotoxicity against MDA-MB-231 and MCF-7 breast cancer cells in both 2D and collagen-based 3D co-cultures, with this advantage maintained under matrix constraints that mimic solid tumor microenvironments. Together, these findings establish substrate mechanics as a tunable and functionally decisive design parameter for engineering durable, solid-tumor-effective CD8+ T cell products in preclinical in vitro models of solid tumors.

immunology↗

bioRxiv2025

A Precisely Controlled Long-Acting Immunosuppression Platform Enables Prolonged Survival of Vascularized Composite Allografts

Vascularized composite allotransplantation (VCA) restores complex tissue defects but demands lifelong systemic immunosuppression. Oral tacrolimus (TAC) is limited by a narrow therapeutic window, pharmacokinetic variability, adherence challenges, and toxicity. Local delivery could mitigate these issues, yet clinical translation has been hindered by burst release, short duration, and the inability to co-deliver agents. We developed PRECISE (Programmable, REtrievable, Controlled ImmunoSuppression Encapsulator), an injectable, in-situ-forming PLGA depot that achieves long-acting, tightly controlled TAC release via structure-guided co-formulation with drug-binding agents (DBAs). GRAS small molecules (e.g., EGCG, maltotriose) identified by in silico docking and in vitro screening suppressed burst and modulated solvent efflux. Notably, rapamycin (RAPA) served dually as an mTOR inhibitor and a TAC-binding excipient, enabling synchronized dual-agent delivery. PRECISE eliminated burst in vitro and produced coordinated TAC+RAPA release with clinically compatible injectability. In rats, monthly intragraft dosing maintained systemic TAC/RAPA within the therapeutic window ([~]5-10 ng/mL) for >300 days, prolonged hindlimb allograft survival, expanded Tregs, and induced donor-specific hyporesponsiveness. Surgical retrieval of the depot triggered rapid TAC decline, demonstrating reversibility. In a stringent, fully MHC-mismatched porcine VCA model, PRECISE maintained on-target drug levels and extended graft survival beyond 90 days with minimal rejection and preserved vascular integrity. PRECISE is, to our knowledge, the first retrievable, injectable platform to deliver long-acting, dual-agent immunosuppression with controlled kinetics, rapid attainment of therapeutic steady state, and sustained graft protection. Its modular, structure-guided design enables clinical translation across VCA and solid-organ transplantation, delivering precise, durable, and safer immunosuppression.

bioengineering↗