Open Access Publications

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Open access publications by faculty, postdocs, and graduate students in the Department of Biomedical Engineering.

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Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer
(Advanced Therapeutics, 2024-04-26) Dang, Megan N.; Suri, Sejal; Li, Kejian; Gomez Casas, Carolina; Stigliano, Gianna; Riley, Rachel S.; Scully, Mackenzie A.; Hoover, Elise C.; Aboeleneen, Sara B.; Kramarenko, George C.; Day, Emily S.
The paucity of targeted therapies for triple-negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular β-catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis. To suppress Wnt signaling in TNBC cells, this work develops therapeutic nanoparticles (NPs) functionalized with FZD7 antibodies and β-catenin small interfering RNAs (siRNAs). The antibodies enable TNBC cell specific binding and inhibit Wnt signaling by locking FZD7 receptors in a ligand unresponsive state, while the siRNAs suppress β-catenin through RNA interference. Compared to NPs coated with antibodies or siRNAs individually, NPs coated with both agents more potently reduce the expression of several Wnt related genes in TNBC cells, leading to greater inhibition of cell proliferation, migration, and spheroid formation. In two murine models of metastatic TNBC, the dual antibody/siRNA nanocarriers outperformed controls in terms of inhibiting tumor growth, metastasis, and recurrence. These findings demonstrate suppressing Wnt signaling at both the receptor and mRNA levels via antibody/siRNA nanocarriers is a promising approach to combat TNBC.
Can axial loading restore in vivo disc geometry, opening pressure, and T2 relaxation time?
(JOR Spine, 2024-04-25) Newman, Harrah R.; Moore, Axel C.; Meadows, Kyle D.; Hilliard, Rachel L.; Boyes, Madeline S.; Vresilovic, Edward J.; Schaer, Thomas P.; Elliott, Dawn M.
Background Cadaveric intervertebral discs are often studied for a variety of research questions, and outcomes are interpreted in the in vivo context. Unfortunately, the cadaveric disc does not inherently represent the LIVE condition, such that the disc structure (geometry), composition (T2 relaxation time), and mechanical function (opening pressure, OP) measured in the cadaver do not necessarily represent the in vivo disc. Methods We conducted serial evaluations in the Yucatan minipig of disc geometry, T2 relaxation time, and OP to quantify the changes that occur with progressive dissection and used axial loading to restore the in vivo condition. Results We found no difference in any parameter from LIVE to TORSO; thus, within 2 h of sacrifice, the TORSO disc can represent the LIVE condition. With serial dissection and sample preparation the disc height increased (SEGMENT height 18% higher than TORSO), OP decreased (POTTED was 67% lower than TORSO), and T2 time was unchanged. With axial loading, an imposed stress of 0.20–0.33 MPa returned the disc to in vivo, LIVE disc geometry and OP, although T2 time was decreased. There was a linear correlation between applied stress and OP, and this was conserved across multiple studies and species. Conclusion To restore the LIVE disc state in human studies or other animal models, we recommend measuring the OP/stress relationship and using this relationship to select the applied stress necessary to recover the in vivo condition.
Intervertebral disc degeneration instigates vertebral endplate remodeling and facet joint pathology in a large animal model
(eCells and Materials, 2024-04-23) Gullbrand, S.E.; Orozco, B.S.; Fainor, M.; Meadows, K.; Hilliard, R.; Boyes, M.; Mahindroo, S.; Mauck, R.L.; Elliott, D.M.; Schaer, T.P.; Smith, H.E.
Although the intervertebral discs are the most studied region of the spinal motion segment with respect to their degeneration and contributions to back pain, it is becoming increasingly evident that degeneration of adjacent structures including the facet joints, vertebral endplates and paraspinal muscles occurs concomitant with disc degeneration. However, crosstalk between these adjacent components of the motion segment remains understudied, particularly in preclinical large animal models. In this study, intervertebral disc degeneration was induced in goat cervical discs via intradiscal injection of 2U or 5U of chondroitinase ABC (ChABC). Disc degeneration and trans-endplate small molecule diffusion into the disc were assessed at 12 weeks using in vivo MRI T2 mapping and post-contrast enhanced T1 mapping. Animals were euthanized at 12 weeks post-ChABC injection for end-term structure-function analysis of the disc, vertebral endplate and facet tissues. Intradiscal injection of ChABC yielded a spectrum of disc degeneration independent of ChABC dosage. Increasing severity of disc degeneration correlated with increased vertebral endplate bone density. In levels that did not exhibit severe degeneration or endplate resorptions, we demonstrated a significant correlation between NP T2 values and disc diffusion properties. Early-stage osteoarthritis of the facet joints was observed concomitant with disc degeneration, characterized primarily by alterations in facet cartilage mechanical properties. This work established a large animal model of whole spinal motion segment degeneration, including correlations between trans-endplate diffusion and disc health, which can be utilized to increase the translational relevance of studies evaluating strategies for disc regeneration or repair.
A Dynamic Gradient Stiffness Material Platform to Manipulate Cardiac Fibroblasts' Spatio-Temporal Behavior
(Advanced Functional Materials, 2024-04-05) Cao, Zheng; Clark, Andy T.; Vite, Alexia; Corbin, Elise A.
After myocardial infarction, there exists a spatiotemporal variation of cardiac tissue stiffness across the infarcted border region outward to remote regions, influencing adverse remodeling and cardiac fibrosis, and this stiffness gradient changes over time. Here, a platform with dynamic, tunable, and reversible gradient stiffness can recapitulate in vitro the time-dependent stiffness range across the infarction border that occurs as part of the remodeling process is presented. This platform enables the observation of time-dependent interaction between cardiac fibroblasts and their mechanical microenvironment in a spatiotemporal manner. Specifically, the competition and cooperation of a chemical cue (antifibrotic drug) and mechanical cue (gradient softening) in tandem to attenuate the fibrotic responses of cardiac fibroblasts is examined. Applying a combined intervention showed either additive or antagonistic effects on fibrosis-related gene regulation compared to separate interventions of drug or softening. This work reveals the spatiotemporal variation of fibrotic response in cardiac fibroblasts as well as the complexity of antifibrotic drug dosing with stiffness changes and their combinatory effect on cardiac fibroblasts. This platform provides a unique in vitro tool to study disease progression mechanisms in a more clinically relevant microenvironment and also serves as a cost-effective model for potential therapeutic screening.
FZD7-Targeted Nanoparticles to Enhance Doxorubicin Treatment of Triple-Negative Breast Cancer
(ACS Omega, 2024-03-16) Hoover, Elise C.; Ruggiero, Olivia M.; Swingler, Rachel N.; Day, Emily S.
Doxorubicin (DOX) is a chemotherapy agent commonly used to treat triple-negative breast cancer (TNBC), but it has insufficient efficacy against the disease and considerable toxicity due to its off-target delivery. To improve the specificity of DOX for TNBC, we encapsulated it in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) coated with antibodies against Frizzled7 (FZD7), a receptor that is overexpressed on TNBC cells and which is a key activator of the Wnt signaling pathway. In vitro studies show that DOX encapsulation does not hinder its ability to localize to the nucleus in human TNBC cell cultures and that DOX delivered via NPs induces apoptosis and DNA damage via H2A.X phosphorylation to the same degree as freely delivered DOX. FZD7-targeted NPs delivering DOX caused significantly greater inhibition of metabolic activity and led to a smaller cell population following treatment when compared to freely delivered DOX or DOX-loaded NPs coated only with poly(ethylene glycol) (PEG). The FZD7 antibodies additionally provided significant levels of Wnt pathway inhibition, as demonstrated by an increase in β-catenin phosphorylation, indicative of β-catenin destruction and downregulation. These results show that FZD7-targeted platforms have great promise for improving the therapeutic window of otherwise toxic chemotherapies like DOX in TNBC and other cancers that display the overexpression of FZD7 receptors.
Growth factors and growth factor gene therapies for treating chronic wounds
(Bioengineering and Translational Medicine, 2023-12-28) Mullin, James A.; Rahmani, Erfan; Kiick, Kristi L.; Sullivan, Millicent O.
Chronic wounds are an unmet clinical need affecting millions of patients globally, and current standards of care fail to consistently promote complete wound closure and prevent recurrence. Disruptions in growth factor signaling, a hallmark of chronic wounds, have led researchers to pursue growth factor therapies as potential supplements to standards of care. Initial studies delivering growth factors in protein form showed promise, with a few formulations reaching clinical trials and one obtaining clinical approval. However, protein-form growth factors are limited by instability and off-target effects. Gene therapy offers an alternative approach to deliver growth factors to the chronic wound environment, but safety concerns surrounding gene therapy as well as efficacy challenges in the gene delivery process have prevented clinical translation. Current growth factor delivery and gene therapy approaches have primarily used single growth factor formulations, but recent efforts have aimed to develop multi-growth factor approaches that are better suited to address growth factor insufficiencies in the chronic wound environment, and these strategies have demonstrated improved efficacy in preclinical studies. This review provides an overview of chronic wound healing, emphasizing the need and potential for growth factor therapies. It includes a summary of current standards of care, recent advances in growth factor, cell-based, and gene therapy approaches, and future perspectives for multi-growth factor therapeutics. Translational Impact Statement Chronic wounds persist as a healthcare challenge despite extensive research on various treatments, including growth factors and gene therapies. Progress in translating these therapeutics to clinical use has been slow, with many growth factor approaches demonstrating promise in preclinical studies but providing limited benefits in clinical trials or clinical application. This review presents recent advances in growth factor therapies and growth factor gene therapies, discusses obstacles to regulatory approval, and offers perspectives on potential innovations for successful clinical translation.
One Pot Photomediated Formation of Electrically Conductive Hydrogels
(ACS Polymers Au, 2024-02-14) Nguyen, Dan My; Lo, Chun-Yuan; Guo, Tianzheng; Choi, Taewook; Sundar, Shalini; Swain, Zachary; Wu, Yuhang; Dhong, Charles; Kayser, Laure V.
Electrically conductive hydrogels represent an innovative platform for the development of bioelectronic devices. While photolithography technologies have enabled the fabrication of complex architectures with high resolution, photoprinting conductive hydrogels is still a challenging task because the conductive polymer absorbs light which can outcompete photopolymerization of the insulating scaffold. In this study, we introduce an approach to synthesizing conductive hydrogels in one step. Our approach combines the simultaneous photo-cross-linking of a polymeric scaffold and the polymerization of 3,4-ethylene dioxythiophene (EDOT), without additional photocatalysts. This process involves the copolymerization of photo-cross-linkable coumarin-containing monomers with sodium styrenesulfonate to produce a water-soluble poly(styrenesulfonate-co-coumarin acrylate) (P(SS-co-CoumAc)) copolymer. Our findings reveal that optimizing the [SS]:[CoumAc] ratio at 100:5 results in hydrogels with the strain at break up to 16%. This mechanical resilience is coupled with an electronic conductivity of 9.2 S m–1 suitable for wearable electronics. Furthermore, the conductive hydrogels can be photopatterned to achieve micrometer-sized structures with high resolution. The photo-cross-linked hydrogels are used as electrodes to record stable and reliable surface electromyography (sEMG) signals. These novel photo-cross-linkable polymers combined with one-pot PEDOT (poly-EDOT) polymerization open possibilities for rapidly prototyping complex bioelectronic devices and creating custom-designed interfaces between electronics and biological systems.
Nanotechnologies for the detection and treatment of endometriosis
(Frontiers in Biomaterials Science, 2023-11-16) Sahni, Maneesha; Day, Emily S.
Endometriosis is an incurable gynecologic disease characterized by endometrial-like tissue growth outside of the uterine cavity. It affects approximately 10% of reproductive age women, who endure pelvic pain during periods and/or sexual intercourse and who suffer from reduced fertility and diminished quality of life due to the side effects of current treatments. To improve the management and prognosis of endometriosis patients, researchers have recently begun to develop nanoparticle-based diagnostics and treatments that are more effective and less invasive than existing approaches. This review discusses the current state of the field and highlights considerations for the continued development of nanotechnologies for the diagnosis and treatment of endometriosis.
Surgical Management of Traumatic Meniscus Injuries
(Pathophysiology, 2023-12-04) Popper, Hannah R.; Fliegel, Brian E.; Elliott, Dawn M.; Su, Alvin W.
The menisci increase the contact area of load bearing in the knee and thus disperse the mechanical stress via their circumferential tensile fibers. Traumatic meniscus injuries cause mechanical symptoms in the knee, and are more prevalent amongst younger, more active patients, compared to degenerative tears amongst the elderly population. Traumatic meniscus tears typically result from the load-and-shear mechanism in the knee joint. The treatment depends on the size, location, and pattern of the tear. For non-repairable tears, partial or total meniscal resection decreases its tensile stress and increases joint contact stress, thus potentiating the risk of arthritis. A longitudinal vertical tear pattern at the peripheral third red-red zone leads to higher healing potential after repair. The postoperative rehabilitation protocols after repair range from immediate weight-bearing with no range of motion restrictions to non-weight bearing and delayed mobilization for weeks. Pediatric and adolescent patients may require special considerations due to their activity levels, or distinct pathologies such as a discoid meniscus. Further biomechanical and biologic evidence is needed to guide surgical management, postoperative rehabilitation protocols, and future technology applications for traumatic meniscus injuries.
Surface Functionalization with (3-Glycidyloxypropyl)trimethoxysilane (GOPS) as an Alternative to Blending for Enhancing the Aqueous Stability and Electronic Performance of PEDOT:PSS Thin Films
(ACS Applied Materials and Interfaces, 2023-11-29) Osazuwa, Peter O.; Lo, Chun-Yuan; Feng, Xu; Nolin, Abigail; Dhong, Charles; Kayser, Laure V.
Organic mixed ionic–electronic conductors, such as poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), are essential materials for the fabrication of bioelectronic devices due to their unique ability to couple and transport ionic and electronic charges. The growing interest in bioelectronic devices has led to the development of organic electrochemical transistors (OECTs) that can operate in aqueous solutions and transduce ionic signals of biological origin into measurable electronic signals. A common challenge with OECTs is maintaining the stability and performance of the PEDOT:PSS films operating under aqueous conditions. Although the conventional approach of blending the PEDOT:PSS dispersions with a cross-linker such as (3-glycidyloxypropyl)trimethoxysilane (GOPS) helps to ensure strong adhesion of the films to device substrates, it also impacts the morphology and thus electrical properties of the PEDOT:PSS films, which leads to a significant reduction in the performance of OECTs. In this study, we instead functionalize only the surface of the device substrates with GOPS to introduce a silane monolayer before spin-coating the PEDOT:PSS dispersion on the substrate. In all cases, having a GOPS monolayer instead of a blend leads to increased electronic performance metrics, such as three times higher electronic conductivity, volumetric capacitance, and mobility–capacitance product [μC*] value in OECT devices, ultimately leading to a record value of 406 ± 39 F cm–1 V–1 s–1 for amorphous PEDOT:PSS. This increased performance does not come at the expense of operational stability, as both the blend and surface functionalization show similar performance when subjected to pulsed gate bias stress, long-term electrochemical cycling tests, and aging over 150 days. Overall, this study establishes a novel approach to using GOPS as a surface monolayer instead of a blended cross-linker, for achieving high-performance organic mixed ionic–electronic conductors that are stable in water for bioelectronics.
Combination cancer imaging and phototherapy mediated by membrane-wrapped nanoparticles
(International Journal of Hyperthermia, 2023-10-30) Aboeleneena, Sara B.; Scully, Mackenzie A.; Kramarenko, George C.; Day, Emily S.
Cancer is a devastating health problem with inadequate treatment options. Many conventional treatments for solid-tumor cancers lack tumor specificity, which results in low efficacy and off-target damage to healthy tissues. Nanoparticle (NP)-mediated photothermal therapy (PTT) is a promising minimally invasive treatment for solid-tumor cancers that has entered clinical trials. Traditionally, NPs used for PTT are coated with passivating agents and/or targeting ligands, but alternative coatings are being explored to enhance tumor specific delivery. In particular, cell-derived membranes have emerged as promising coatings that improve the biointerfacing of photoactive NPs, which reduces their immune recognition, prolongs their systemic circulation and increases their tumor accumulation, allowing for more effective PTT. To maximize treatment success, membrane-wrapped nanoparticles (MWNPs) that enable dual tumor imaging and PTT are being explored. These multifunctional theranostic NPs can be used to enhance tumor detection and/or ensure a sufficient quantity of NPs that have arrived in the tumor prior to laser irradiation. This review summarizes the current state-of-the-art in engineering MWNPs for combination cancer imaging and PTT and discusses considerations for the path toward clinical translation.
Fundamental limits of parasitoid-driven host population suppression: Implications for biological control
(PLoS ONE, 2023-12-22) Singh, Abhyudai
Parasitoid wasps are increasingly being used to control insect pest populations, where the pest is the host species parasitized by the wasp. Here we use the discrete-time formalism of the Nicholson-Bailey model to investigate a fundamental question—are there limits to parasitoid-driven suppression of the host population density while still ensuring a stable coexistence of both species? Our model formulation imposes an intrinsic self-limitation in the host’s growth resulting in a carrying capacity in the absence of the parasitoid. Different versions of the model are considered with parasitism occurring at a developmental stage that is before, during, or after the growth-limiting stage. For example, the host’s growth limitation may occur at its larval stage due to intraspecific competition, while the wasps attack either the host egg, larval or pupal stage. For slow-growing hosts, models with parasitism occurring at different life stages are identical in terms of their host suppression dynamics but have contrasting differences for fast-growing hosts. In the latter case, our analysis reveals that wasp parasitism occurring after host growth limitation yields the lowest pest population density conditioned on stable host-parasitoid coexistence. For ecologically relevant parameter regimes we estimate this host suppression to be roughly 10-20% of the parasitoid-free carrying capacity. We further expand the models to consider a fraction of hosts protected from parasitism (i.e., a host refuge). Our results show that for a given host reproduction rate there exists a critical value of protected host fraction beyond which, the system dynamics are stable even for high levels of parasitism that drive the host to arbitrary low population densities. In summary, our systematic analysis sheds key insights into the combined effects of density-dependence in host growth and parasitism refuge in stabilizing the host-parasitoid population dynamics with important implications for biological control.
Genome-wide screening reveals metabolic regulation of stop-codon readthrough by cyclic AMP
(Nucleic Acids Research, 2023-09-06) Lyu, Zhihui; Villanueva, Patricia; O’Malley, Liam; Murphy, Parker; Augenstreich, Jacques; Briken, Volker; Singh, Abhyudai; Ling, Jiqiang
Translational fidelity is critical for microbial fitness, survival and stress responses. Much remains unknown about the genetic and environmental control of translational fidelity and its single-cell heterogeneity. In this study, we used a high-throughput fluorescence-based assay to screen a knock-out library of Escherichia coli and identified over 20 genes critical for stop-codon readthrough. Most of these identified genes were not previously known to affect translational fidelity. Intriguingly, we show that several genes controlling metabolism, including cyaA and crp, enhance stop-codon readthrough. CyaA catalyzes the synthesis of cyclic adenosine monophosphate (cAMP). Combining RNA sequencing, metabolomics and biochemical analyses, we show that deleting cyaA impairs amino acid catabolism and production of ATP, thus repressing the transcription of rRNAs and tRNAs to decrease readthrough. Single-cell analyses further show that cAMP is a major driver of heterogeneity in stop-codon readthrough and rRNA expression. Our results highlight that carbon metabolism is tightly coupled with stop-codon readthrough. Graphical Abstract available at: https://doi.org/10.1093/nar/gkad725
Validating the measurement of upper limb sensorimotor behavior utilizing a tablet in neurologically intact controls and individuals with chronic stroke
(Journal of NeuroEngineering and Rehabilitation, 2023-09-01) Austin, Devin Sean; Dixon, Makenna J.; Tulimieri, Duncan Thibodeau; Cashaback, Joshua G. A.; Semrau, Jennifer A.
Background Intact sensorimotor function of the upper extremity is essential for successfully performing activities of daily living. After a stroke, upper limb function is often compromised and requires rehabilitation. To develop appropriate rehabilitation interventions, sensitive and objective assessments are required. Current clinical measures often lack precision and technological devices (e.g. robotics) that are objective and sensitive to small changes in sensorimotor function are often unsuitable and impractical for performing home-based assessments. Here we developed a portable, tablet-based application capable of quantifying upper limb sensorimotor function after stroke. Our goal was to validate the developed application and accompanying data analysis against previously validated robotic measures of upper limb function in stroke. Methods Twenty individuals with stroke, twenty age-matched older controls, and twenty younger controls completed an eight-target Visually Guided Reaching (VGR) task using a Kinarm Robotic Exoskeleton and a Samsung Galaxy Tablet. Participants completed eighty trials of the VGR task on each device, where each trial consisted of making a reaching movement to one of eight pseudorandomly appearing targets. We calculated several outcome parameters capturing various aspects of sensorimotor behavior (e.g., Reaction Time, Initial Direction Error, Max Speed, and Movement Time) from each reaching movement, and our analyses compared metric consistency between devices. We used the previously validated Kinarm Standard Analysis (KSA) and a custom in-house analysis to calculate each outcome parameter. Results We observed strong correlations between the KSA and our custom analysis for all outcome parameters within each participant group, indicating our custom analysis accurately replicates the KSA. Minimal differences were observed for between-device comparisons (tablet vs. robot) in our outcome parameters. Additionally, we observed similar correlations for each device when comparing the Fugl-Meyer Assessment (FMA) scores of individuals with stroke to tablet-derived metrics, demonstrating that the tablet can capture clinically-based elements of upper limb impairment. Conclusions Tablet devices can accurately assess upper limb sensorimotor function in neurologically intact individuals and individuals with stroke. Our findings validate the use of tablets as a cost-effective and efficient assessment tool for upper-limb function after stroke.
Modeling the Maturation of the Vocal Fold Lamina Propria Using a Bioorthogonally Tunable Hydrogel Platform
(Advanced Healthcare Materials, 2023-08-02) Zou, Xiaoyu; Zhang, He; Benson, Jamie M.; Gao, Hanyuan; Burris, David L.; Fox, Joseph. M.; Jia, Xinqiao
Toward the goal of establishing an engineered model of the vocal fold lamina propria (LP), mesenchymal stem cells (MSCs) are encapsulated in hyaluronic acid (HA)-based hydrogels employing tetrazine ligation with strained alkenes. To mimic matrix stiffening during LP maturation, diffusion-controlled interfacial bioorthogonal crosslinking is carried out on the soft cellular construct using HA modified with a ferocious dienophile, trans-cyclooctene (TCO). Cultures are maintained in MSC growth media for 14 days to afford a model of a newborn LP that is homogeneously soft (nLP), a homogeneously stiffened construct zero (sLP0) or 7 days (sLP7) post cell encapsulation, and a mature LP model (mLP) with a stiff top layer and a soft bottom layer. Installation of additional HA crosslinks restricts cell spreading. Compared to the nLP controls, sLP7 conditions upregulate the expression of fibrous matrix proteins (Col I, DCN, and FN EDA), classic fibroblastic markers (TNC, FAP, and FSP1), and matrix remodeling enzymes (MMP2, TIMP1, and HAS3). Day 7 stiffening also upregulates the catabolic activities, enhances ECM turnover, and promotes YAP expression. Overall, in situ delayed matrix stiffening promotes a fibroblast transition from MSCs and enhances YAP-regulated mechanosensing.
Sequence-Encoded Differences in Phase Separation Enable Formation of Resilin-like Polypeptide-Based Microstructured Hydrogels
(Biomacromolecules, 2023-08-14) Patkar, Sai S.; Garcia, Cristobal Garcia; Palmese, Luisa L.; Kiick, Kristi L.
Microstructured hydrogels are promising platforms to mimic structural and compositional heterogeneities of the native extracellular matrix (ECM). The current state-of-the-art soft matter patterning techniques for generating ECM mimics can be limited owing to their reliance on specialized equipment and multiple time- and energy-intensive steps. Here, a photocross-linking methodology that traps various morphologies of phase-separated multicomponent formulations of compositionally distinct resilin-like polypeptides (RLPs) is reported. Turbidimetry and quantitative 1H NMR spectroscopy were utilized to investigate the sequence-dependent liquid–liquid phase separation of multicomponent solutions of RLPs. Differences between the intermolecular interactions of two different photocross-linkable RLPs and a phase-separating templating RLP were exploited for producing microstructured hydrogels with tunable control over pore diameters (ranging from 1.5 to 150 μm) and shear storage moduli (ranging from 0.2 to 5 kPa). The culture of human mesenchymal stem cells demonstrated high viability and attachment on microstructured hydrogels, suggesting their potential for developing customizable platforms for regenerative medicine applications.
Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how)
(Journal of Orthopaedic Research, 2023-09-18) Little, Dianne; Amadio, Peter C.; Awad, Hani A.; Cone, Stephanie G.; Dyment, Nathaniel A.; Fisher, Matthew B.; Huang, Alice H.; Koch, Drew W.; Kuntz, Andrew F.; Madi, Rashad; McGilvray, Kirk; Schnabel, Lauren V.; Shetye, Snehal S.; Thomopoulos, Stavros; Zhao, Chunfeng; Soslowsky, Louis J.
Several tendon and ligament animal models were presented at the 2022 Orthopaedic Research Society Tendon Section Conference held at the University of Pennsylvania, May 5 to 7, 2022. A key objective of the breakout sessions at this meeting was to develop guidelines for the field, including for preclinical tendon and ligament animal models. This review summarizes the perspectives of experts for eight surgical small and large animal models of rotator cuff tear, flexor tendon transection, anterior cruciate ligament tear, and Achilles tendon injury using the framework: “Why, Who, What, Where, When, and How” (5W1H). A notable conclusion is that the perfect tendon model does not exist; there is no single gold standard animal model that represents the totality of tendon and ligament disease. Each model has advantages and disadvantages and should be carefully considered in light of the specific research question. There are also circumstances when an animal model is not the best approach. The wide variety of tendon and ligament pathologies necessitates choices between small and large animal models, different anatomic sites, and a range of factors associated with each model during the planning phase. Attendees agreed on some guiding principles including: providing clear justification for the model selected, providing animal model details at publication, encouraging sharing of protocols and expertise, improving training of research personnel, and considering greater collaboration with veterinarians. A clear path for translating from animal models to clinical practice was also considered as a critical next step for accelerating progress in the tendon and ligament field.
Isocorrole-Loaded Polymer Nanoparticles for Photothermal Therapy under 980 nm Light Excitation
(ACS Omega, 2022-10-18) Marek, Maximilian R. J.; Pham, Trong-Nhan; Wang, Jianxin; Cai, Qiuqi; Yap, Glenn P. A.; Day, Emily S.; Rosenthal, Joel
Photothermal therapy (PTT) is a promising treatment option for diseases, including cancer, arthritis, and periodontitis. Typical photothermal agents (PTAs) absorb light in the near-infrared (NIR)-I region of 650–900 nm with a predominant focus around 800 nm, as these wavelengths are minimally absorbed by water and blood in the tissue. Recently, interest has grown in developing nanomaterials that offer more efficient photothermal conversion and that can be excited by light close to or within the NIR-II window of 1000–1700 nm, which offers less absorption by melanin. Herein, we report on the development of 5,5-diphenyl isocorrole (5-DPIC) complexes containing either Zn(II) or Pd(II) (Zn[5-DPIC] and Pd[5-DPIC], respectively) that absorb strongly across the 850–1000 nm window. We also show that poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with these designer isocorroles exhibit low toxicity toward triple-negative breast cancer (TNBC) cells in the dark but enable efficient heat production and photothermal cell ablation upon excitation with 980 nm light. These materials represent an exciting new platform for 980 nm activated PTT and demonstrate the potential for designer isocorroles to serve as effective PTAs.
Matrix Degradability Contributes to the Development of Salivary Gland Progenitor Cells with Secretory Functions
(ACS Applied Materials and Interfaces, 2023-07-12) Metkari, Apoorva S.; Fowler, Eric W.; Witt, Robert L.; Jia, Xinqiao
Synthetic matrices that are cytocompatible, cell adhesive, and cell responsive are needed for the engineering of implantable, secretory salivary gland constructs to treat radiation induced xerostomia or dry mouth. Here, taking advantage of the bioorthogonality of the Michael-type addition reaction, hydrogels with comparable stiffness but varying degrees of degradability (100% degradable, 100DEG; 50% degradable, 50DEG; and nondegradable, 0DEG) by cell-secreted matrix metalloproteases (MMPs) were synthesized using thiolated HA (HA-SH), maleimide (MI)-conjugated integrin-binding peptide (RGD-MI), and MI-functionalized peptide cross-linkers that are protease degradable (GIW-bisMI) or nondegradable (GIQ-bisMI). Organized multicellular structures developed readily in all hydrogels from dispersed primary human salivary gland stem cells (hS/PCs). As the matrix became progressively degradable, cells proliferated more readily, and the multicellular structures became larger, less spherical, and more lobular. Immunocytochemical analysis showed positive staining for stem/progenitor cell markers CD44 and keratin 5 (K5) in all three types of cultures and positive staining for the acinar marker α-amylase under 50DEG and 100DEG conditions. Quantitatively at the mRNA level, the expression levels of key stem/progenitor markers KIT, KRT5, and ETV4/5 were significantly increased in the degradable gels as compared to the nondegradable counterparts. Western blot analyses revealed that imparting matrix degradation led to >3.8-fold increase in KIT expression by day 15. The MMP-degradable hydrogels also promoted the development of a secretary phenotype, as evidenced by the upregulation of acinar markers α-amylase (AMY), aquaporin-5 (AQP5), and sodium-potassium chloride cotransporter 1 (SLC12A2). Collectively, we show that cell-mediated matrix remodeling is necessary for the development of regenerative pro-acinar progenitor cells from hS/PCs.
Individual Muscle Force Estimation in the Human Forearm Using Multi-Muscle MR Elastography (MM-MRE)
(IEEE Transactions on Biomedical Engineering, 2023-06-06) Smith, Daniel R.; Helm, Cody A.; Zonnino, Andrea; McGarry, Matthew D.J.; Johnson, Curtis L.; Sergi, Fabrizio
Objective: To establish the sensitivity of magnetic resonance elastography (MRE) to active muscle contraction in multiple muscles of the forearm. Methods: We combined MRE of forearm muscles with an MRI-compatible device, the MREbot, to simultaneously measure the mechanical properties of tissues in the forearm and the torque applied by the wrist joint during isometric tasks. We measured shear wave speed of thirteen forearm muscles via MRE in a series of contractile states and wrist postures and fit these outputs to a force estimation algorithm based on a musculoskeletal model. Results: Shear wave speed changed significantly upon several factors, including whether the muscle was recruited as an agonist or antagonist (p = 0.0019), torque amplitude (p = <0.0001), and wrist posture (p = 0.0002). Shear wave speed increased significantly during both agonist (p = <0.0001) and antagonist (p = 0.0448) contraction. Additionally, there was a greater increase in shear wave speed at greater levels of loading. The variations due to these factors indicate the sensitivity to functional loading of muscle. Under the assumption of a quadratic relationship between shear wave speed and muscle force, MRE measurements accounted for an average of 70% of the variance in the measured joint torque. Conclusion: This study shows the ability of MM-MRE to capture variations in individual muscle shear wave speed due to muscle activation and presents a method to estimate individual muscle force through MM-MRE derived measurements of shear wave speed. Significance: MM-MRE could be used to establish normal and abnormal muscle co-contraction patterns in muscles of the forearm controlling hand and wrist function.

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