Melissa L Knothe Tate

Scopus Publications

Cell Biophysics–Physiological Contexts, from Organism to Cell, In Vivo to In Silico Models: One Collaboratory’s Perspective
Melissa L. Knothe Tate, Sara McBride-Gagyi, Eric J. Anderson, Lucy Ngo
Biophysica, 2026
Here we present a retrospective, integrative review of the approaches and discoveries of our “collaboratory”, a meta-laboratory comprising cross-disciplinary collaborations across laboratories at fourteen different universities and clinics in seven different countries with shared lead investigators. By tying together insights from four decades of research and discovery, applied across cell types, as well as different tissues, organ systems, and organisms, we have aimed to elucidate the interplay between organisms’ movement and the physiology of their tissues, organs, and organ systems’ resident cells. We highlight the potential of increasing imaging and computing power, as well as machine learning/artificial intelligence approaches, to delineate the Laws of Biology. Codifying these laws will provide a foundation for the future, to promote not only the discovery of underpinning mechanisms but also the sustainability of our natural resources, from our brains to our bones, which serve as veritable “hard drives”, physically rendering a lifetime of cellular experiences and millennia of evolution.
Rivers of Tears – Convergent, Multi-Scale Approaches to Monitor and Optimize the Health of Our World's Inhabitants
Eric J. Anderson, Vittorio Sansalone, Luke P. Lee, Rebecca Grainger, Sohie Lee, et al.
Global Challenges, 2026
The connectivity and interdependence of our world and its inhabitants’ health have come under increasing focus. Elucidation of the common and interdependent mechanisms of health and disease requires approaches that facilitate understanding of complex systems behavior and probing of both individual and collective system parameters. To this end, multiscale physical and computational modeling offers a particularly powerful tool to predict behavior over vast time and length scales. Other novel technologies, e.g., rapid isolation nanotechnology developed to analyze nanoscale small extracellular vesicles in ocular tears, enable tracking of “fingerprints” from diseases as diverse as ocular to neurodegenerative (e.g., dementia) and cancer. In the future, it will be possible to track the health and disease of ecosystems and their inhabitants, using geospatial and epidemiological approaches, as well as novel biotechnologies, to prevent and mitigate disease processes and enhance well‐being. These concepts are applied by way of an exemplary approach to understand and address the impact of toxic, recalcitrant manmade chemicals (i.e., PFAS) on the health of ecosystems and their diverse inhabitants. Such convergent efforts will be necessary and a priority for solving the complex problems threatening the health of our planet and its inhabitants.
Stem cell mechanoadaptation. II. Microtubule stabilization and substrate compliance effects on cytoskeletal remodeling
Vina D. L. Putra, Kristopher A. Kilian, Melissa L. Knothe Tate
APL Bioengineering, 2025
Stem cells adapt to their local mechanical environment by rearranging their cytoskeleton, which underpins the evolution of their shape and fate as well as the emergence of tissue structure and function. Here, in the second part of a two-part experimental series, we aimed to elucidate spatiotemporal cytoskeletal remodeling and resulting changes in morphology and mechanical properties of cells and their nuclei. Akin to mechanical testing of the most basic living and adapting unit of life, i.e., the cell, in situ in model tissue templates, we probed native and microtubule-stabilized (via Paclitaxel, PAX, exposure) stem cells' cytoskeletal adaptation capacity on substrates of increasing compliance (exerting local tension on cells) and with increased target seeding densities (exerting local compression on cells). On 10 and 100 kPa gels, cells seeded at 5000 cells/cm2 and cells proliferated to 15 000 cells/cm2 exhibited bulk moduli that nearly matched those of their respective substrates; hence, they exhibited a greater increase in Young's Modulus after microtubule stabilization than cells cultured on glass. Culture on compliant substrates also reduced microtubule-stabilized cells' F-actin, and microtubule concentration increases compared to cells seeded on glass. On gels, F-actin alignment decreased as more randomly oriented, short actin crosslinks were observed, representing emergent adaptation to the compliant substrate, mediated through myosin II contractility. We conclude that stem cell adaptation to compliant substrates facilitates the accommodation of larger loads from the PAX-stabilized polymerizing microtubule, which, in turn, exerts a larger effect in determining cells' capacity to stiffen and remodel the cytoskeleton. Taken as a whole, these studies establish correlations between cytoskeleton and physical and mechanical parameters of stem cells. Hence, the studies progress our understanding of the dynamic cytoskeleton as well as shape changes in cells and their nuclei, culminating in emergent tissue development and healing.
Stem cell mechanoadaptation. I. Effect of microtubule stabilization and volume changing stresses on cytoskeletal remodeling
Vina D. L. Putra, Kristopher A. Kilian, Melissa L. Knothe Tate
APL Bioengineering, 2025
Here, we report on the first part of a two-part experimental series to elucidate spatiotemporal cytoskeletal remodeling, which underpins the evolution of stem cell shape and fate, and the emergence of tissue structure and function. In Part I of these studies, we first develop protocols to stabilize microtubules exogenously using paclitaxel (PAX) in a standardized model murine embryonic stem cell line (C3H/10T1/2) to maximize comparability with previously published studies. We then probe native and microtubule-stabilized stem cells' capacity to adapt to volume changing stresses effected by seeding at increasing cell densities, which emulates local compression and tissue template formation during development. Within the concentration range of 1–100 nM, microtubule-stabilized stem cells maintain viability and reduce proliferation. PAX stabilization of microtubules is associated with increased cell volume as well as flattening of the cell and nucleus. Compared to control cells, microtubule-stabilized cells exhibit thick, bundled microtubules and highly aligned, thicker and longer F-actin fibers, corresponding to an increase in the Young's modulus of the cell. Both F-actin and microtubule concentration increase with increasing PAX concentration, whereby the increase in F-actin is more prominent in the basal region of the cell. The corresponding increase in microtubule is observed more globally across the apical and basal region of the cell. Seeding at increasing target densities induces local compression on cells. This increase in local compression modulates cell volume and concomitant increases in F-actin and microtubule concentration to a greater degree than microtubule stabilization via PAX. Cells seeded at high density exhibit higher bulk modulus than corresponding cells seeded at low density. These data demonstrate the capacity of stem cells to adapt to an interplay of mechanical and chemical cues, i.e., respective compression and exogenous microtubule stabilization; the resulting cytoskeletal remodeling manifests as evolution of mechanical properties relevant to development of multicellular tissue constructs.
Interface tissues of the mesoderm: Periosteum, ligament, interosseous membrane, & myofascial tissues, an inspiration for next generation medical textiles
Sotiria Anastopolous, Lucy Ngo, Joanna Ng, Vina Putra, Melissa L. Knothe Tate
Current Opinion in Biomedical Engineering, 2024
A spike in circulating cytokines TNF-α and TGF-β alters barrier function between vascular and musculoskeletal tissues
Lucy Ngo, Melissa L. Knothe Tate
Scientific Reports, 2023
Molecular transport between the circulatory and musculoskeletal systems regulates articular joint physiology in health and disease. Osteoarthritis (OA) is a degenerative joint disease linked to systemic and local inflammation. Inflammatory events involve cytokines, which are secreted by cells of the immune system and modulate molecular transport across tissue interfaces (referred to as tight junction [TJ] barrier function). In a previous study from our group, OA knee joint tissues were shown to exhibit size separation of different sized molecules delivered as a single bolus to the heart (Ngo et al. in Sci. Rep. 8:10254, 2018). Here, in a follow up study of parallel design, we test the hypothesis that two common cytokines, with multifaceted roles in the etiology of osteoarthritis as well as immune state in general, modulate the barrier function properties of joint tissue interfaces. Specifically, we probe the effect of an acute cytokine increase (spike) on molecular transport within tissues and across tissue interfaces of the circulatory and musculoskeletal systems. A single bolus of fluorescent-tagged 70 kDa dextran, was delivered intracardially, either alone, or with either the pro-inflammatory cytokine TNF-α or the anti-inflammatory cytokine TGF-β, to skeletally mature (11 to 13-month-old) guinea pigs (Dunkin-Hartley, a spontaneous OA animal model). After five minutes' circulation, whole knee joints were serial sectioned and fluorescent block face cryo-imaged at near-single-cell resolution. The 70 kDa fluorescent-tagged tracer is analogous in size to albumin, the most prevalent blood transporter protein, and quantification of tracer fluorescence intensity gave a measure of tracer concentration. Within five minutes, a spike (acute doubling) in circulating cytokines TNF-α or TGF-β significantly disrupted barrier function between the circulatory and musculoskeletal systems, with barrier function essentially abrogated in the TNF-α group. In the entire volume of the joint (including all tissue compartments and the bounding musculature), tracer concentration was significantly decreased in the TGF-β- and TNF-α- compared to the control-group. These studies implicate inflammatory cytokines as gatekeepers for molecular passage within and between tissue compartments of our joints and may open new means to delay the onset and mitigate the progression of degenerative joint diseases such as OA, using pharmaceutical and/or physical measures.
Biomechanical, biophysical and biochemical modulators of cytoskeletal remodelling and emergent stem cell lineage commitment
Vina D. L. Putra, Kristopher A. Kilian, Melissa L. Knothe Tate
Communications Biology, 2023
Across complex, multi-time and -length scale biological systems, redundancy confers robustness and resilience, enabling adaptation and increasing survival under dynamic environmental conditions; this review addresses ubiquitous effects of cytoskeletal remodelling, triggered by biomechanical, biophysical and biochemical cues, on stem cell mechanoadaptation and emergent lineage commitment. The cytoskeleton provides an adaptive structural scaffold to the cell, regulating the emergence of stem cell structure-function relationships during tissue neogenesis, both in prenatal development as well as postnatal healing. Identification and mapping of the mechanical cues conducive to cytoskeletal remodelling and cell adaptation may help to establish environmental contexts that can be used prospectively as translational design specifications to target tissue neogenesis for regenerative medicine. In this review, we summarize findings on cytoskeletal remodelling in the context of tissue neogenesis during early development and postnatal healing, and its relevance in guiding lineage commitment for targeted tissue regeneration. We highlight how cytoskeleton-targeting chemical agents modulate stem cell differentiation and govern responses to mechanical cues in stem cells’ emerging form and function. We further review methods for spatiotemporal visualization and measurement of cytoskeletal remodelling, as well as its effects on the mechanical properties of cells, as a function of adaptation. Research in these areas may facilitate translation of stem cells’ own healing potential and improve the design of materials, therapies, and devices for regenerative medicine.
Paclitaxel release from hollow PMMA nanoparticles: Factors affecting release rate as quantified via dialysis and membrane centrifugation
Theatin van Leeuwen, Rhiannon P. Kuchel, Melissa L. Knothe Tate, Per B. Zetterlund
Colloids and Surfaces A Physicochemical and Engineering Aspects, 2023
Connectomics of Bone to Brain—Probing Physical Renderings of Cellular Experience
Melissa L. Knothe Tate, Abhilash Srikantha, Christian Wojek, Dirk Zeidler
Frontiers in Physiology, 2021
“Brainless” cells, the living constituents inhabiting all biological materials, exhibit remarkably smart, i.e., stimuli-responsive and adaptive, behavior. The emergent spatial and temporal patterns of adaptation, observed as changes in cellular connectivity and tissue remodeling by cells, underpin neuroplasticity, muscle memory, immunological imprinting, and sentience itself, in diverse physiological systems from brain to bone. Connectomics addresses the direct connectivity of cells and cells’ adaptation to dynamic environments through manufacture of extracellular matrix, forming tissues and architectures comprising interacting organs and systems of organisms. There is imperative to understand the physical renderings of cellular experience throughout life, from the time of emergence, to growth, adaptation and aging-associated degeneration of tissues. Here we address this need through development of technological approaches that incorporate cross length scale (nm to m) structural data, acquired via multibeam scanning electron microscopy, with machine learning and information transfer using network modeling approaches. This pilot case study uses cutting edge imaging methods for nano- to meso-scale study of cellular inhabitants within human hip tissue resected during the normal course of hip replacement surgery. We discuss the technical approach and workflow and identify the resulting opportunities as well as pitfalls to avoid, delineating a path for cellular connectomics studies in diverse tissue/organ environments and their interactions within organisms and across species. Finally, we discuss the implications of the outlined approach for neuromechanics and the control of physical behavior and neuromuscular training.
Osteoarthritis: New Strategies for Transport and Drug Delivery across Length Scales
Lucy Ngo, Melissa L. Knothe Tate
ACS Biomaterials Science and Engineering, 2020
Osteoarthritis (OA) is the fourth leading cause of disability in adults. Yet, few viable pharmaceutical options exist for pain abatement and joint restoration, aside from joint replacement at late and irreversible stages of the disease. From the first onset of OA, as joint pain increases, individuals with arthritis increasingly reach for drug delivery solutions, from taking oral glycosaminoglycans (GAGs) bought over the counter from retail stores (e.g., Costco) to getting injections of viscous, GAG-containing synovial fluid supplement in the doctor's office. Little is known regarding the efficacy of delivery mode and/or treatment by such disease-modulating agents. This Review addresses the interplay of mechanics and biology on drug delivery to affected joints, which has profound implications for molecular transport in joint health and (patho)physiology. Multiscale systems biology approaches lend themselves to understand the relationship between the cell and joint health in OA and other joint (patho)physiologies. This Review first describes OA-related structural and functional changes in the context of the multilength scale anatomy of articular joints. It then summarizes and categorizes, by size and charge, published molecular transport studies, considering changes in permeability induced through inflammatory pathways. Finally, pharmacological interventions for OA are outlined in the context of molecular weights and modes of drug delivery. Taken together, the current state-of-the-art points to a need for new drug delivery strategies that harness systems-based interactions underpinning molecular transport and maintenance of joint structure and function at multiple length scales from molecular agents to cells, tissues, and tissue compartments which together make up articular joints. Cutting edge and cross-length and -time scale imaging represents a key discovery enabling technology in this process.
Advanced Design and Manufacture of Mechanoactive Materials Inspired by Skin, Bones, and Skin-on-Bones
Melissa Louise Knothe Tate
Frontiers in Bioengineering and Biotechnology, 2020
In vitro biocompatibility and biomechanics study of novel, Microscopy Aided Designed and ManufacturEd (MADAME) materials emulating natural tissue weaves and their intrinsic gradients
Joanna L. Ng, Vina D.L. Putra, Melissa L. Knothe Tate
Journal of the Mechanical Behavior of Biomedical Materials, 2020
Mechanomics Approaches to Understand Cell Behavior in Context of Tissue Neogenesis, During Prenatal Development and Postnatal Healing
Vina D. L. Putra, Min Jae Song, Sarah McBride-Gagyi, Hana Chang, Kate Poole, et al.
Frontiers in Cell and Developmental Biology, 2020
Mapping the Mechanome–A Protocol for Simultaneous Live Imaging and Quantitative Analysis of Cell Mechanoadaptation and Ingression
Vina Putra, Iman Jalilian, Madeline Campbell, Kate Poole, Renee Whan, et al.
Bio Protocol, 2019
Biotextilogy - Prototyping and testing mechanical gradient textiles that emulate Nature's own
Joanna L. Ng, Tegtaranjit Singh, Lawrence C. Kwan, Melissa L. Knothe Tate
Results in Materials, 2019
Electron Microscopy Sample Preparation Protocol Enabling Nano-to-mesoscopic Mapping of Cellular Connectomes and Their Habitats in Human Tissues and Organs
Lucy Ngo, Anton Nathanson, Tomasz Garbowski, Ulf Knothe, Dirk Zeidler, et al.
Bio Protocol, 2019
Comprehensive pressure profiling to develop next-generation compression treatment for lymphedema: Testing efficacy of high resolution sensors
Daniel J. Hageman, Shuying Wu, Daniel Latimer, Karen Virdi, Chun H. Wang, et al.
Sensors and Actuators A Physical, 2019
Knee joint tissues effectively separate mixed sized molecules delivered in a single bolus to the heart
Lucy Ngo, Lillian E. Knothe, Melissa L. Knothe Tate
Scientific Reports, 2018
Biotechnologies toward Mitigating, Curing, and Ultimately Preventing Edema through Compression Therapy
Daniel J. Hageman, Shuying Wu, Sharon Kilbreath, Stanley G. Rockson, Chun Wang, et al.
Trends in Biotechnology, 2018
Prospective design, rapid prototyping, and testing of smart dressings, drug delivery patches, and replacement body parts using Microscopy Aided Design and ManufacturE (MADAME)
Hans Jörg Sidler, Jacob Duvenage, Eric J. Anderson, Joanna Ng, Daniel J. Hageman, et al.
Frontiers in Medicine, 2018
Engineering mechanical gradients in next generation biomaterials – Lessons learned from medical textile design
Joanna L. Ng, Ciara E. Collins, Melissa L. Knothe Tate
Acta Biomaterialia, 2017
Establishing the basis for mechanobiology-based physical therapy protocols to potentiate cellular healing and tissue regeneration
Joanna L. Ng, Mariana E. Kersh, Sharon Kilbreath, M. Knothe Tate
Frontiers in Physiology, 2017
Scale-up of nature's tissue weaving algorithms to engineer advanced functional materials
Joanna L. Ng, Lillian E. Knothe, Renee M. Whan, Ulf Knothe, Melissa L. Knothe Tate
Scientific Reports, 2017
Live tissue imaging to elucidate mechanical modulation of stem cell niche quiescence
Nicole Y.C. Yu, Connor A. O’Brien, Iveta Slapetova, Renee M. Whan, Melissa L. Knothe Tate
Stem Cells Translational Medicine, 2017
Translating periosteum’s regenerative power: Insights from quantitative analysis of tissue genesis with a periosteum substitute implant
Shannon R. Moore, Céline Heu, Nicole Y.C. Yu, Renee M. Whan, Ulf R. Knothe, et al.
Stem Cells Translational Medicine, 2016

MOST CITED SCHOLAR PUBLICATIONS

The osteocyte
MLK Tate, JR Adamson, AE Tami, TW Bauer
The international journal of biochemistry & cell biology 36 (1), 1-8 , 2004
2004
Citations: 639
"Whither flows the fluid in bone?" An osteocyte's perspective
ML Knothe Tate
J Biomech 36, 1409-1424 , 2003
2003
Citations: 445
In vivo tracer transport through the lacunocanalicular system of rat bone in an environment devoid of mechanical loading.
MLT Knothe, P Niederer, U Knothe
Bone 22 (2), 107-117 , 1998
1998
Citations: 346
High‐resolution, high‐throughput imaging with a multibeam scanning electron microscope
AL Eberle, S Mikula, R Schalek, J Lichtman, MLK Tate, D Zeidler
Journal of microscopy 259 (2), 114-120 , 2015
2015
Citations: 337
Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches
C Colnot, X Zhang, MLK Tate
Journal of Orthopaedic Research 30 (12), 1869-1878 , 2012
2012
Citations: 320
In Vivo Demonstration of Load-Induced Fluid Flow in the Rat Tibia and Its Potential Implications For Processes Associated With Functional Adaptation
MLK Tate, R Steck, MR Forwood, P Niederer
Journal of Experimental Biology 203 (18), 2737-2745 , 2000
2000
Citations: 310
Concise review: the periosteum: tapping into a reservoir of clinically useful progenitor cells
H Chang, ML Knothe Tate
Stem cells translational medicine 1 (6), 480-491 , 2012
2012
Citations: 242
An ex vivo model to study transport processes and fluid flow in loaded bone
MLK Tate, U Knothe
Journal of Biomechanics 33 (2), 247-254 , 2000
2000
Citations: 225
Flow-induced stress on adherent cells in microfluidic devices
J Shemesh, I Jalilian, A Shi, GH Yeoh, MLK Tate, ME Warkiani
Lab on a Chip 15 (21), 4114-4127 , 2015
2015
Citations: 181
Experimental elucidation of mechanical load-induced fluid flow and its potential role in bone metabolism and functional adaptation
MLK Tate, ULF Knothe, P Niederer
The American journal of the medical sciences 316 (3), 189-195 , 1998
1998
Citations: 181
The influence of mechanical stimulus on the pattern of tissue differentiation in a long bone fracture—an FEM study
TN Gardnera, T Stoll, L Marks, S Mishra, MK Tate
Journal of biomechanics 33 (4), 415-425 , 2000
2000
Citations: 167
Mechanical modulation of osteochondroprogenitor cell fate
MLK Tate, TD Falls, SH McBride, R Atit, UR Knothe
The international journal of biochemistry & cell biology 40 (12), 2720-2738 , 2008
2008
Citations: 146
The role of interstitial fluid flow in the remodeling response to fatigue loading
AE Tami, P Nasser, O Verborgt, MB Schaffler, MLK Tate
Journal of Bone and Mineral Research 17 (11), 2030-2037 , 2002
2002
Citations: 146
Probing the tissue to subcellular level structure underlying bone's molecular sieving function
AE Tami, MB Schaffler, ML Knothe Tate
Biorheology 40 (6), 577-590 , 2003
2003
Citations: 136
Modulation of stem cell shape and fate B: mechanical modulation of cell shape and gene expression
SH McBride, T Falls, ML Knothe Tate
Tissue Engineering Part A 14 (9), 1573-1580 , 2008
2008
Citations: 134
Modulation of stem cell shape and fate A: the role of density and seeding protocol on nucleus shape and gene expression
SH McBride, ML Knothe Tate
Tissue Engineering Part A 14 (9), 1561-1572 , 2008
2008
Citations: 133
Biomechanical, biophysical and biochemical modulators of cytoskeletal remodelling and emergent stem cell lineage commitment
VDL Putra, KA Kilian, ML Knothe Tate
Communications Biology 6 (1), 75 , 2023
2023
Citations: 132
Idealization of pericellular fluid space geometry and dimension results in a profound underprediction of nano-microscale stresses imparted by fluid drag on osteocytes
EJ Anderson, MLK Tate
Journal of biomechanics 41 (8), 1736-1746 , 2008
2008
Citations: 130
Nano–microscale models of periosteocytic flow show differences in stresses imparted to cell body and processes
EJ Anderson, S Kaliyamoorthy, JID Alexander, MLK Tate
Annals of biomedical engineering 33 (1), 52-62 , 2005
2005
Citations: 130
Testing of a new one-stage bone-transport surgical procedure exploiting the periosteum for the repair of long-bone defects
MLK Tate, TF Ritzman, E Schneider, UR Knothe
JBJS 89 (2), 307-316 , 2007
2007
Citations: 124

Melissa L Knothe Tate

Scopus Publications

RECENT SCHOLAR PUBLICATIONS

MOST CITED SCHOLAR PUBLICATIONS