Milica Radisic

University of Toronto | U of T · Institute of Biomaterials and Biomedical Engineering

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitocho...

Epicardial cells (EPIs) form the outer layer of the heart and play an important role in development and disease. Current heart‐on‐a‐chip platforms still do not fully mimic the native cardiac environment due to the absence of relevant cell types, such as EPIs. Here, using the Biowire II platform, engineered cardiac tissues with an epicardial outer l...

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In recent years, the structural analysis of tissue elements has gained significant importance in biomedical research. Advancements in imaging technologies have created a pressing need to quantify tissue and cell properties accurately. This paper introduces a MATLAB-based analytical tool designed to measure a spectrum of properties from 2D images of...

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or di...

Despite tremendous progress in the development of mature heart-on-a-chip models, human cell–based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced acute myocarditis. We observed hallmarks of...

The substantial economic impact of non-healing wounds, scarring, and burns stemming from skin injuries is evident, resulting in a financial burden on both patients and the healthcare system. This review paper provides an overview of the skin’s vital role in guarding against various environmental challenges as the body’s largest protective organ and...

Cells and tissues in their native environment are organized into intricate fractal structures, which are rarely recapitulated in their culture in vitro. The extent to which fractal patterns that resemble complex topography in vivo influence cell maturation, and the cellular responses to such shape stimulation remain inadequately elucidated. Yet, th...

Artificial organs and organs‐on‐a‐chip (OoC) are of great clinical and scientific interest and have recently been made by additive manufacturing, but depend on, and benefit from, biocompatible, biodegradable, and soft materials. Poly(octamethylene maleate (anhydride) citrate (POMaC) meets these criteria and has gained popularity, and as in principl...

Application of cardiac patches to the heart surface can be undertaken to provide support and facilitate regeneration of the damaged cardiac tissue following ischemic injury. Biomaterial composition is an important consideration in the design of cardiac patch materials as it governs host response to ultimately prevent the undesirable fibrotic respon...

The successful translation of organ-on-a-chip devices requires the development of an automated workflow for device fabrication, which is challenged by the need for precise deposition of multiple classes of materials in micro-meter scaled configurations. Many current heart-on-a-chip devices are produced manually, requiring the expertise and dexterit...

Recent advances in both cardiac tissue engineering and hearts‐on‐a‐chip are grounded in new biomaterial development as well as the employment of innovative fabrication techniques that enable precise control of the mechanical, electrical, and structural properties of the cardiac tissues being modelled. The elongated structure of cardiomyocytes requi...

Vascular diseases, such as atherosclerosis and thrombosis, are major causes of morbidity and mortality worldwide. Traditional in vitro models for studying vascular diseases have limitations, as they do not fully recapitulate the complexity of the in vivo microenvironment. Organ-on-a-chip systems have emerged as a promising approach for modeling vas...

Cardiovascular tissue constructs provide unique design requirements due to their functional responses to substrate mechanical properties and cyclic stretching behavior of cardiac tissue that requires the use of durable elastic materials. Given the diversity of polyester synthesis approaches, an opportunity exists to develop a new class of biocompat...

Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of my...

Coronavirus disease 2019 (COVID‐19) has been a major global health concern since its emergence in 2019, with over 680 million confirmed cases as of April 2023. While COVID‐19 has been strongly associated with the development of cardiovascular complications, the specific mechanisms by which viral infection induces myocardial dysfunction remain large...

Human cardiac bioengineering has traditionally focused on cardiomyocyte differentiation and maturation. Unlike normal cardiac growth in the native human heart, human pluripotent stem cell (hPSC)- derived cardiomyocytes are typically grown in the absence of key supportive populations, which may negatively impact function due to a failure to recreate...

To better understand sodium channel (SCN5A)-related cardiomyopathies, we generated ventricular cardiomyocytes from induced pluripotent stem cells obtained from a dilated cardiomyopathy patient harbouring the R222Q mutation, which is only expressed in adult SCN5A isoforms. Because the adult SCN5A isoform was poorly expressed, without functional diff...

We developed a heart-on-a-chip platform that integrates highly flexible, vertical, 3D micropillar electrodes for electrophysiological recording and elastic microwires for the tissue’s contractile force assessment. The high aspect ratio microelectrodes were 3D-printed into the device using a conductive polymer, poly(3,4-ethylenedioxythiophene): poly...

Artificial organs and organs-on-a-chip are of great clinical and scientific interest and have recently been made by additive manufacturing, but depend on, and benefit from, biocompatible, biodegradable, and soft materials. Poly(octamethylene maleate (anhydride) citrate (POMaC) meets these criteria and has gained popularity, and as in principle, it...

Hypertrophic cardiomyopathy (HCM) is mainly caused by sarcomere gene variants in MYH7 and MYBPC3. Targeted drugs like myosin ATPase inhibitors have shown efficacy in adult HCM but have not been evaluated in children. We generated iPSC-cardiomyocytes (CMs) from four children with HCM harboring variants in MYH7 ( V606M; R453C) or MYBPC3 (G148R; P955f...

We review the emergence of the new field of organ-on-a-chip (OOAC) engineering, from the parent fields of tissue engineering and microfluidics. We place into perspective the tools and capabilities brought into the OOAC field by early tissue engineers and microfluidics experts. Liver-on-a-chip and heart-on-a-chip are used as two case studies of syst...

By providing an ideal environment for healing, biomaterials can be designed to facilitate and encourage wound regeneration. As the wound healing process is complex, there needs to be consideration for the cell types playing major roles, such as fibroblasts. As a major cell type in the dermis, fibroblasts have a large impact on the processes and out...

Biomimicking In article 2201346 by Milica Radisic and co‐workers, scaffolds fabricated by coaxial printing of bioelastomers can mimic both the structures and mechanical properties of native tissues, which are ideal for organ‐on‐a‐chip and tissue engineering applications. This image shows an artistic tubular structure made of a biodegradable elastom...

Conical Cardiac Ventricle In article 2101165, Radisic and co‐workers describe a multilayered in vitro model of a cardiac ventricle composed of three layers with different pattern orientations representing the physiological cardiac fiber architecture. This model is fabricated by rolling a 2D elastomeric scaffold seeded with cardiomyocytes around a c...

Human fibrotic diseases constitute a major health problem worldwide. Fibrosis involves significant etiological heterogeneity and encompasses a wide spectrum of diseases affecting various organs. To date, many fibrosis targeted therapeutic agents failed due to inadequate efficacy and poor prognosis. In order to dissect disease mechanisms and develop...

Bioelastomers are extensively used in biomedical applications due to their desirable mechanical strength, tunable properties, and chemical versatility; however, three‐dimensional (3D) printing bioelastomers into microscale structures has proven elusive. Herein, a high throughput omnidirectional printing approach via coaxial extrusion is described t...

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold tremendous promise for in vitro modeling to assess native myocardial function and disease mechanisms as well as testing drug safety and efficacy. However, current iPSC- CMs are functionally immature, resembling in vivo CMs of fetal or neonatal developmental states. The use of targ...

Poor quality (eg. excessive scarring) or delayed closure of skin wounds can have profound physical and pyschosocial effects on patients as well as pose an enormous economic burden on the healthcare system. An effective means of improving both the rate and quality of wound healing is needed for all patients suffering from skin injury. Despite wound...

Despite current efforts in organ‐on‐chip engineering to construct miniature cardiac models, they often lack some physiological aspects of the heart, including fiber orientation. This motivates the development of bioartificial left ventricle models that mimic the myofiber orientation of the native ventricle. Herein, an approach relying on microfabri...

Cell-based models that mimic in vivo heart physiology are poised to make significant advances in cardiac disease modeling and drug discovery. In these systems, cardiomyocyte (CM) contractility is an important functional metric, but current measurement methods are inaccurate, low-throughput, or require complex set-ups. To address this need, we devel...

Despite capturing the imagination of scientists for decades, the goal of creating an artificial heart for transplantation proved to be significantly more challenging than initially anticipated. Toward this goal, recent ground-breaking studies demonstrate the development of functional left ventricular (LV) models. LV models are artificially construc...

Background Endothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe coronavirus disease 2019 (COVID-19), indicating that the vasculature is affected during the acute stages of SARS-CoV-2 infection. It remains unknown whether circulating vascular markers are sufficient to predi...

Background Endothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe COVID-19, indicating that the vasculature is affected during the acute stages of SARS-CoV-2 infection. It remains unknown whether circulating vascular markers are sufficient to predict clinical outcomes, are u...

This chapter provides a brief review of different microfabricated platforms for in vitro modeling of cardiac tissue. The initial focus is on the materials used to generate cardiac microtissues, considering both the type of cells and hydrogels used, as well as the scaffolds for evaluating the tissues themselves. The focus then shifts to the microfab...

Microfluidic polymeric blood vessel captures the adverse effects of SARS-CoV-2 on vasculature and enables identification of a therapeutic peptide that abolished virus induced cytokine storm orchestrated by the immune cells.

Extensive progress has been made in developing engineered models for elucidating human cardiac disease. Cardiac fibrosis is often associated with all forms of cardiac disease and has a direct deleterious effect on cardiac function. As currently there is no effective therapeutic strategy specifically designed to target fibrosis, in vitro diagnostic...

The convergence of tissue engineering and patient-specific stem cell biology has enabled the engineering of in vitro tissue models that allow the study of patient-tailored treatment modalities. However, sex-related disparities in health and disease, from systemic hormonal influences to cellular-level differences, are often overlooked in stem cell b...

We explore the utility of bioengineered human tissues-individually or connected into physiological units-for biological research. While much smaller and simpler than their native counterparts, these tissues are complex enough to approximate distinct tissue phenotypes: molecular, structural, and functional. Unlike organoids, which form spontaneously...

Despite showing a great promise in the field of nanomedicine, nanoparticles have gained a significant attention from regulatory agencies regarding their possible adverse health effects upon environmental exposure. Whether those nanoparticles are generated through intentional or unintentional means, the constant exposure to nanomaterials can inevita...

Cardiovascular diseases are the leading cause of death worldwide. Discovering new therapies to treat heart disease requires improved understanding of cardiac physiology at a cellular level. Extracellular vesicles (EVs) are plasma membrane-bound nano- and microparticles secreted by cells and known to play key roles in intercellular communication, of...

Epithelial-to-mesenchymal transition (EMT) is a process that occurs in a wide range of tissues and environments, in response to numerous factors and conditions, and plays a critical role in development, disease, and regeneration. The process involves epithelia transitioning into a mobile state and becoming mesenchymal cells. The investigation of EM...

Angiotensin II (Ang II) presents a critical mediator in various pathological conditions such as non-genetic cardiomyopathy. Osmotic pump infusion in rodents is a commonly used approach to model cardiomyopathy associated with Ang II. However, profound differences in electrophysiology and pharmacokinetics between rodent and human cardiomyocytes may l...

A sound understanding of developmental biology is part of the foundation of effective stem cell‐derived tissue engineering. Here, the key concepts of cardiac development that are successfully applied in a bioinspired approach to growing engineered cardiac tissues, are reviewed. The native cardiac milieu is studied extensively from embryonic to adul...

Owing to their high spatiotemporal precision and adaptability to different host cells, organ-on-a-chip systems are showing great promise in drug discovery, developmental biology studies and disease modeling. However, many current micro-engineered biomimetic systems are limited in technological application because of culture media mixing that does n...

A state-of-the-art organ-on-a-chip system enabled co-culture of highly oxygen-sensitive Faecalibacterium prausnitzii with human intestinal epithelial cells, recapitulating a critical role of the bacteria in the maintenance of anti-inflammatory phenotype of gut epithelium mediated by bacteria-secreted butyrate.

The equine distal limb wound healing model, characterized by delayed re-epithelialization and a fibroproliferative response to wounding similar to that observed in humans, is a valuable tool for the study of biomaterials poised for translation into both the veterinary and human medical markets. In the current study, we developed a novel method of b...

Accumulating evidence indicates that air pollution contributes to serious and fatal damage to the cardiovascular system, yet the mechanisms that drive air pollution associated cardiovascular disease and dysfunction remain unclear. In an effort to create a more predictive in vitro model, a 3D platform, known as integrated vasculature for assessing d...

Itaconate (ITA) is an emerging powerhouse of innate immunity with therapeutic potential that is limited in its ability to be administered in a soluble form. A library of polyester materials that incorporate ITA into polymer backbones resulting in materials with inherent immunoregulatory behavior is developed. Harnessing hydrolytic degradation relea...

Strategies to regenerate cardiac tissue postinjury are limited and heart transplantation remains the only 'cure' for a failing heart. Extracellular vesicles (EVs), membrane-bound cell secretions important in intercellular signaling, have been shown to play a crucial role in regulating heart function. A mechanistic understanding of the role of EVs i...

Study of the molecular basis of myocardial fibrosis is hampered by limited access to tissues from human patients and by confounding variables associated with sample accessibility, collection, processing and storage. Here, we report an integrative strategy based on mass spectrometry for the phosphoproteomic profiling of normal and fibrotic cardiac t...

In article number 2000046, Milica Radisic and co‐workers design a biomaterial patch that incorporates an adhesive component to improve attachment. To achieve this, a novel polymer is synthesized with elastic properties tailored for cardiac patch applications and enhanced adhesion to tissue. In terms of application, this material is used to fabricat...

Tumor progression relies on the interaction between neoplastic epithelial cells and their surrounding stromal partners. This cell cross‐talk affects stromal development, and ultimately the heterogeneity impacts drug efficacy. To mimic this evolving paradigm, 3D vascularized pancreatic adenocarcinoma tissue is microengineered in a tri‐culture system...

In order to secure biomaterials to tissue surfaces, sutures or glues are commonly used. Of interest is the development of a biomaterial patch for applications in tissue engineering and regeneration that incorporates an adhesive component to simplify patch application and ensure sufficient adhesion. A separate region dedicated to fulfilling the spec...

Kidney-on-a-chip devices may revolutionize the discovery of new therapies. However, fabricating a 3D glomerulus remains a challenge, due to a requirement for a microscale soft material with complex topography to support cell culture in a native configuration. Here, we describe the use of microfluidic spinning to recapitulate complex concave and con...

To accelerate the cardiac drug discovery pipeline, we set out to develop a platform that would be capable of quantifying tissue-level functions such as contractile force and be amenable to standard multiwell-plate manipulations. We report a 96-well-based array of 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues - termed Cardiac Mi...

The development of novel 3D tissue culture systems has enabled the in vitro study of in vivo processes, thereby overcoming many of the limitations of previous 2D tissue culture systems. Advances in biomaterials, including the discovery of novel synthetic polymers has allowed for the generation of physiologically relevant in vitro 3D culture models....

Biomaterials are becoming increasingly crucial for healthcare solutions, with extensive use in the field of tissue engineering and drug delivery. After implantation, biomaterials trigger an immune response characterized by the recruitment of bone‐marrow‐derived proinflammatory macrophages that develop as the most abundant cell type surrounding the...

Objective Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells–derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in r...

Bioelastomers have been extensively used in tissue engineering applications due to favorable mechanical stability, tunable properties and chemical versatility. As these materials generally possess low elastic modulus and relatively long gelation time, it is challenging to 3D print them using traditional techniques. Instead, the field of 3D printing...

Modeling of human organs has long been a task for scientists in order to lower the costs of therapeutic development and understand the pathological onset of human disease. For decades, despite marked differences in genetics and etiology, animal models remained the norm for drug discovery and disease modeling. Innovative biofabrication techniques ha...

In the developed world, cardiovascular disease is responsible for the loss of more human lives than all cancer combined. Due to the minimal intrinsic ability of adult heart to regenerate itself following injury, the myocardial infarction results in rapid death of hundreds of millions of cardiomyocytes (CMs), and vigorous inflammatory response. Over...

Researchers have combined organ-on-a-chip engineering with the benefits of organoids to make improved models of the human retina.

Organ-level vascularization has been a long-standing challenge in the field of tissue engineering. Recent advances, particularly in the use of projection stereolithography and food colors as photoabsorbers are highlighted, as are several recent studies on the clinical translation of engineered vasculature.

A viscoelastic adhesive cardiac patch with optimal mechanical behaviour, determined using a computational model, restores heart function and slows down pathological remodelling following myocardial infarction in rodents.

In article number 1900245 by Milica Radisic and co‐workers, poly(itaconate‐co‐citrate‐co‐octanediol) (PICO) polyester bioelastomers are developed with tunable elasticity and rapid photocrosslinking for soft biomaterial applications. Leveraging a two‐step curing process, PICO materials are moldable into intricate scaffold designs capable of supporti...

Synthetic polyester elastomeric constructs have become increasingly important for a range of healthcare applications, due to tunable soft elastic properties that mimic those of human tissues. A number of these constructs require intricate mechanical design to achieve a tunable material with controllable curing. Here, the synthesis and characterizat...

Currently, the clinic is faced with the difficult task of treating non-healing wounds. While the treatment regimen varies between different patients and wounds, a non-healing wound can be a significant detriment to a patient’s quality of life, thus highlighting the need for more effective treatments. The immune system is heavily involved in regulat...

Optimal levels of chaos and fractality are distinctly associated with physiological health and function in natural systems. Chaos is a type of nonlinear dynamics that tends to exhibit seemingly random structures, whereas fractality is a measure of the extent of organization underlying such structures. Growing bodies of work are demonstrating both t...

Myocardial fibrosis is a severe global health problem due to its prevalence in all forms of cardiac diseases and direct role in causing heart failure. The discovery of efficient antifibrotic compounds has been hampered due to the lack of a physiologically relevant disease model. Herein, we present a disease model of human myocardial fibrosis and us...

Microphysiological systems (MPSs) have been proposed as an improved tool to recreate the complex biological features of the native niche with the goal of improving in vitro-in vivo extrapolation. In just over a decade, MPS technologies have progressed from single-tissue chips to multitissue plates with integrated pumps for perfusion. Concurrently,...

Organ-on-a-chip systems have the potential to revolutionize drug screening and disease modeling through the use of human stem cell-derived cardiomyocytes. The predictive power of these tissue models critically depends on the functional assembly and maturation of human cells that are used as building blocks for organ-on-a-chip systems. To resemble a...

To accelerate the cardiac drug discovery pipeline, we set out to develop a platform that would be amenable to standard multiwell-plate manipulations and be capable of quantifying tissue-level functions such as contractile force. We report a 96-well-based array of 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues - termed Cardiac Mi...

In article number 1801187 by Milica Radisic, Boyang Zhang, and co‐workers, a scalable, functional, and 96‐well plate compatible platform is presented with innovative multimaterial processing. Three classes of materials are integrated, including built‐in electrodes to drive electrical stimulation for tissue maturation and induce tissue contraction d...

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing un...

Due to escalating drug developmental costs and limitations of cardiotoxicity screening, there is an urgent need to develop robust in vitro 3D tissue culture platforms that can both facilitate the culture of human cardiac tissues and provide noninvasive functional readouts predictive of cardiotoxicity in clinical settings. However, such platforms co...

Cardiovascular disease is the leading cause of death worldwide. Although investment in drug discovery and development has been sky-rocketing, the number of approved drugs has been declining. Cardiovascular toxicity due to therapeutic drug use claims the highest incidence and severity of adverse drug reactions in late-stage clinical development. The...

Most kidney diseases begin with abnormalities in glomerular podocytes, motivating the need for podocyte models to study pathophysiological mechanisms and new treatment options. However, podocytes cultured in vitro face a limited ability to maintain appreciable extents of differentiation hallmarks, raising concerns over the relevance of study result...

Microengineered biomimetic systems for organ-on-a-chip or tissue engineering purposes often fail as a result of an inability to recapitulate the in vivo environment, specifically the presence of a well-defined vascular system. To address this limitation, we developed an alternative method to cultivate three-dimensional (3D) tissues by incorporating...

Predicting the effects of drugs before human clinical trials is at the heart of drug screening and discovery processes. The cost of drug discovery is steadily increasing owing to the limited predictability of 2D cell culture and animal models. The convergence of microfabrication and tissue engineering gave rise to organ-on-a-chip technologies, whic...

Some of the most significant leaps in the history of modern civilization-the development of article in China, the steam engine, which led to the European industrial revolution, and the era of computers-have occurred when science converged with engineering. Recently, the convergence of human pluripotent stem cell technology with biomaterials and bio...

Wound healing is a highly complex process of tissue repair that relies on the synergistic effect of a number of different cells, cytokines, enzymes, and growth factors. A deregulation in this process can lead to the formation of a non-healing chronic ulcer. Current treatment options, such as collagen wound dressings, are unable to meet the demand s...

Using the methods described herein, we have demonstrated how scaffolds can be designed for a number of applications including tissue engineering, biomedical devices and injectable tissues. Details on the methods of polymerization, physical and chemical characterization of poly(octamethylene maleate (anhydride) citrate (POMaC) are described. Two POM...

Nanomaterials have been used in a wide range of biomedical research fields, such as delivery of biomolecules, biosensing, bioimaging, and tissue scaffolding. These materials have also emerged in some biotechnology products and in preclinical/clinical trials for humans. Increasing use of nanomaterials in science and technology and consequently their...

In article 1703524, Milica Radisic, Boyang Zhang, and co-workers present a user-friendly 96-well plate platform (InVADE, Integrated Vasculature for Assessing Dynamic Events) that utilizes a single vascularized scaffold to replicate in vivo like drug transfer and cell trafficking between multiple organs. Offering highly reproducible in vivo simulati...

Vasculature is an essential component of physiologically relevant tissue, yet mimicking the native vasculature is an ongoing challenge in tissue engineering. Microfabrication may provide a solution. This technique allows for control of material design and architecture at the micron scale, which in turn enables the incorporation of microscale cues t...

MSCs are widely applied to regenerate heart tissue in myocardial diseases but when grown in standard two-dimensional (2D) cultures exhibit limited potential for cardiac repair and develop fibrogenic features with increasing culture time. MSCs can undergo partial cardiomyogenic differentiation, which improves their cardiac repair capacity. When appl...

Primers used for real-time PCR. ACTA/αSMA, alpha smooth muscle actin; BMP4, bone morphogenic protein 4; CCL5/ RANTES, C-C motif chemokine ligand 5; COL1A1, collagen type 1 alpha 1; CTGF, connective tissue growth factor; CXCL10/IP10, C-X-C motif chemokine ligand 10; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HGF, hepatocyte growth factor; IDO1...