Fabrication of Synthetic Mesenchymal Stem Cells for the Treatment of Acute Myocardial Infarction in Mice.

RATIONALE: Stem cell therapy faces several challenges. It is difficult to grow, preserve, and transport stem cells before they are administered to the patient. Synthetic analogs for stem cells represent a new approach to overcome these hurdles and hold the potential to revolutionize regenerative medicine. OBJECTIVE: We aim to fabricate synthetic analogs of stem cells and test their therapeutic potential for treatment of acute myocardial infarction in mice. METHODS AND RESULTS: We packaged secreted factors from human bone marrow-derived mesenchymal stem cells (MSC) into poly(lactic-co-glycolic acid) microparticles and then coated them with MSC membranes. We named these therapeutic particles synthetic MSC (or synMSC). synMSC exhibited a factor release profile and surface antigens similar to those of genuine MSC. synMSC promoted cardiomyocyte functions and displayed cryopreservation and lyophilization stability in vitro and in vivo. In a mouse model of acute myocardial infarction, direct injection of synMSC promoted angiogenesis and mitigated left ventricle remodeling. CONCLUSIONS: We successfully fabricated a synMSC therapeutic particle and demonstrated its regenerative potential in mice with acute myocardial infarction. The synMSC strategy may provide novel insight into tissue engineering for treating multiple diseases.

Angiopellosis as an Alternative Mechanism of Cell Extravasation.

Stem cells possess the ability to home in and travel to damaged tissue when injected intravenously. For the cells to exert their therapeutic effect, they must cross the blood vessel wall and enter the surrounding tissues. The mechanism of extravasation injected stem cells employ for exit has yet to be characterized. Using intravital microscopy and a transgenic zebrafish line Tg(fli1a:egpf) with GFP-expressing vasculature, we documented the detailed extravasation processes in vivo for injected stem cells in comparison to white blood cells (WBCs). While WBCs left the blood vessels by the standard diapedesis process, injected cardiac and mesenchymal stem cells underwent a distinct method of extravasation that was markedly different from diapedesis. Here, the vascular wall undergoes an extensive remodeling to allow the cell to exit the lumen, while the injected cell remains distinctively passive in activity. We termed this process Angio-pello-sis, which represents an alternative mechanism of cell extravasation to the prevailing theory of diapedesis. Stem Cells 2017;35:170-180 Video Highlight: https://youtu.be/i5EI-ZvhBps.

EGaIn-Modified ePADs for Simultaneous Detection of Homocysteine and C-Reactive Protein in Saliva toward Early Diagnosis of Cardiovascular Disease.

Homocysteine (Hcy) and C-reactive protein (CRP) are critical biomarkers for numerous chronic diseases, with cardiovascular disease (CVD) being the most prevalent. The ability to simultaneously detect both biomarkers in point-of-care settings is in high demand for CVD early diagnosis and prevention. Herein, we prepared the eutectic gallium indium (EGaIn) nanoparticles decorated with p-phenylenediamine (PPD) on the surface to facilitate the subsequent attachment of gold nanoparticles (AuNPs) to achieve EGaIn-PPD@Au, which was modified on the screen-printed electrochemical paper-based analytical devices (ePADs). Aptamers that are specific to Hcy and CRP were then immobilized on the EGaIn-PPD@Au surface to achieve the sensing interface on ePADs. The presence of EGaIn-PPD@Au significantly enhanced the electrical conductivity, leading to amplified electrochemical signals. This aptasensor demonstrated high specificity, capable of detecting Hcy in a range of 1-50 µM with a detection limit of 0.22 µM, and the detection range for CRP was 1-100 ng/mL with a detection limit of 0.039 ng/mL. The aptasensor also effectively detected Hcy and CRP in clinical saliva samples, yielding an area under the curve (AUC) of about 0.80 when the individual biomarker was considered and 0.93 when both biomarkers were taken into account. The positive correlation observed between salivary and blood concentrations of Hcy and CRP, coupled with their association with cardiovascular disease (CVD), suggested the potential of this methodology as a noninvasive point-of-care strategy for the early diagnosis of CVD.

Plant-Derived Biomaterials and Their Potential in Cardiac Tissue Repair.

Cardiovascular disease remains the leading cause of mortality worldwide. The inability of cardiac tissue to regenerate after an infarction results in scar tissue formation, leading to cardiac dysfunction. Therefore, cardiac repair has always been a popular research topic. Recent advances in tissue engineering and regenerative medicine offer promising solutions combining stem cells and biomaterials to construct tissue substitutes that could have functions similar to healthy cardiac tissue. Among these biomaterials, plant-derived biomaterials show great promise in supporting cell growth due to their inherent biocompatibility, biodegradability, and mechanical stability. More importantly, plant-derived materials have reduced immunogenic properties compared to popular animal-derived materials (e.g., collagen and gelatin). In addition, they also offer improved wettability compared to synthetic materials. To date, limited literature is available to systemically summarize the progression of plant-derived biomaterials in cardiac tissue repair. Herein, this paper highlights the most common plant-derived biomaterials from both land and marine plants. The beneficial properties of these materials for tissue repair are further discussed. More importantly, the applications of plant-derived biomaterials in cardiac tissue engineering, including tissue-engineered scaffolds, bioink in 3D biofabrication, delivery vehicles, and bioactive molecules, are also summarized using the latest preclinical and clinical examples.

Advances in Extrusion 3D Bioprinting: A Focus on Multicomponent Hydrogel-Based Bioinks.

3D bioprinting involves the combination of 3D printing technologies with cells, growth factors and biomaterials, and has been considered as one of the most advanced tools for tissue engineering and regenerative medicine (TERM). However, despite multiple breakthroughs, it is evident that numerous challenges need to be overcome before 3D bioprinting will eventually become a clinical solution for a variety of TERM applications. To produce a 3D structure that is biologically functional, cell-laden bioinks must be optimized to meet certain key characteristics including rheological properties, physico-mechanical properties, and biofunctionality; a difficult task for a single component bioink especially for extrusion based bioprinting. As such, more recent research has been centred on multicomponent bioinks consisting of a combination of two or more biomaterials to improve printability, shape fidelity and biofunctionality. In this article, multicomponent hydrogel-based bioink systems are systemically reviewed based on the inherent nature of the bioink (natural or synthetic hydrogels), including the most current examples demonstrating properties and advances in application of multicomponent bioinks, specifically for extrusion based 3D bioprinting. This review article will assist researchers in the field in identifying the most suitable bioink based on their requirements, as well as pinpointing current unmet challenges in the field.

Tailoring of cardiovascular stent material surface by immobilizing exosomes for better pro-endothelialization function.

Stent intervention as available method in clinic has been widely applied for cardiovascular disease treatment for decades. However, the restenosis caused by late thrombosis and hyperplasia still limits the stents long-term application, and the essential cause is usually recognized as endothelial functionalization insufficiency of the stent material surface. Here, we address this limitation by developing a pro-endothelial-functionalization surface that immobilized a natural factors-loaded nanoparticle, exosome, onto the poly-dopamine (PDA) coated materials via electrostatic binding. This PDA/Exosome surface not only increased the endothelial cells number on the materials, but also improved their endothelial function, including platelet endothelial cell adhesion molecule-1 (CD31) expression, cell migration and nitric oxide release. The pro-inflammation macrophage (M1 phenotype) attachment and synthetic smooth muscle cell proliferation as the interference factors for the endothelialization were not only inhibited by the PDA/Exosome coating, while the cells were also regulated to anti-inflammation macrophage (M2 phenotype) and contractile smooth muscle cell, which may contribute to endothelialization. Thus, it can be summarized this method has potential application on surface modification of cardiovascular biomaterials.

NIPAM-based Microgel Microenvironment Regulates the Therapeutic Function of Cardiac Stromal Cells.

To tune the chemical, physical, and mechanical microenvironment for cardiac stromal cells to treat acute myocardial infarction (MI), we prepared a series of thermally responsive microgels with different surface charges (positive, negative, and neutral) and different degrees of hydrophilicity, as well as functional groups (carboxyl, hydroxyl, amino, and methyl). These microgels were used as injectable hydrogels to create an optimized microenvironment for cardiac stromal cells (CSCs). Our results indicated that a hydrophilic and negatively charged microenvironment created from poly( N-isopropylacrylamide- co-itaconic acid) was favorable for maintaining high viability of CSCs, promoting CSC proliferation and facilitating the formation of CSC spheroids. A large number of growth factors, such as vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-1), and stromal-derived factor-1 (SDF-1) were released from the spheroids, promoting neonatal rat cardiomyocyte activation and survival. After injecting the poly( N-isopropylacrylamide- co-itaconic acid) microgel into mice, we examined their acute inflammation and T-cell immune reactions. The microgel itself did not elicit obvious immune response. We then injected the same microgel-encapsulated with CSCs into MI mice. The result revealed the treatment-promoted MI heart repair through angiogenesis and inhibition of apoptosis with an improved cell retention rate. This study will open a door for tailoring poly( N-isopropylacrylamide)-based microgel as a delivery vehicle for CSC therapy.

A Regenerative Cardiac Patch Formed by Spray Painting of Biomaterials onto the Heart.

Layering a regenerative polymer scaffold on the surface of the heart, termed as a cardiac patch, has been proven to be effective in preserving cardiac function after myocardial infarction (MI). However, the placement of such a patch on the heart usually needs open-chest surgery, which is traumatic, therefore prevents the translation of this strategy into the clinic. We sought to device a way to apply a cardiac patch by spray painting in situ polymerizable biomaterials onto the heart with a minimally invasive procedure. To prove the concept, we used platelet fibrin gel as the "paint" material in a mouse model of MI. The use of the spraying system allowed for placement of a uniform cardiac patch on the heart in a mini-invasive manner without the need for sutures or glue. The spray treatment promoted cardiac repair and attenuated cardiac dysfunction after MI.

Heart Repair Using Nanogel-Encapsulated Human Cardiac Stem Cells in Mice and Pigs with Myocardial Infarction.

Stem cell transplantation is currently implemented clinically but is limited by low retention and engraftment of transplanted cells and the adverse effects of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Here, we demonstrate the safety and efficacy of encapsulating human cardiac stem cells (hCSCs) in thermosensitive poly(N-isopropylacrylamine-co-acrylic acid) or P(NIPAM-AA) nanogel in mouse and pig models of myocardial infarction (MI). Unlike xenogeneic hCSCs injected in saline, injection of nanogel-encapsulated hCSCs does not elicit systemic inflammation or local T cell infiltrations in immunocompetent mice. In mice and pigs with acute MI, injection of encapsulated hCSCs preserves cardiac function and reduces scar sizes, whereas injection of hCSCs in saline has an adverse effect on heart healing. In conclusion, thermosensitive nanogels can be used as a stem cell carrier: the porous and convoluted inner structure allows nutrient, oxygen, and secretion diffusion but can prevent the stem cells from being attacked by immune cells.