Biomaterials for direct cardiac repair-A rapid scoping review 2012-2022.

A plethora of biomaterials for heart repair are being tested worldwide for potential clinical application. These therapeutics aim to enhance the quality of life of patients with heart disease using various methods to improve cardiac function. Despite the myriad of therapeutics tested, only a minority of these studied biomaterials have entered clinical trials. This rapid scoping review aims to analyze literature available from 2012 to 2022 with a focus on clinical trials using biomaterials for direct cardiac repair, i.e., where the intended function of the biomaterial is to enhance the repair of the endocardium, myocardium, epicardium or pericardium. This review included neither biomaterials related to stents and valve repair nor biomaterials serving as vehicles for the delivery of drugs. Surprisingly, the literature search revealed that only 8 different biomaterials mentioned in 23 different studies out of 7038 documents (journal articles, conference abstracts or clinical trial entries) have been tested in clinical trials since 2012. All of these, intended to treat various forms of ischaemic heart disease (heart failure, myocardial infarction), were of natural origin and most used direct injections as their delivery method. This review thus reveals notable gaps between groups of biomaterials tested pre-clinically and clinically. STATEMENT OF SIGNIFICANCE: Rapid scoping review of clinical application of biomaterials for cardiac repair. 7038 documents screened; 23 studies mention 8 different biomaterials only. Biomaterials for repair of endocardium, myocardium, epicardium or pericardium. Only 8 different biomaterials entered clinical trials in the past 10 years. All of the clinically translated biomaterials were of natural origin.

Decellularization of Pig Lung to Yield Three-Dimensional Scaffold for Lung Tissue Engineering.

Lately, the need for three-dimensional (3D) cell culture has been recognized in order to closely mimic the organization of native tissues. Thus, 3D scaffolds started to be employed to facilitate the 3D cell organization and enable the artificial tissue formation for the emerging tissue engineering applications. 3D scaffolds can be prepared by various techniques, each with certain advantages and disadvantages. Decellularization is an easy method based on removal of cells from native tissue sample, yielding extracellular matrix (ECM) scaffold with preserved architecture and bioactivity. This chapter provides a detailed protocol for decellularization of pig lung and also some basic assays for evaluation of its effectivity, such as determination of DNA content and histological verification of the selected ECM components. Such decellularized scaffold can subsequently be used for various tissue engineering applications, for example, for recellularization with cells of interest, for natural ECM hydrogel preparation, or as a bioink for 3D bioprinting.

Phenylpropanoid Content of Chickpea Seed Coats in Relation to Seed Dormancy.

The physical dormancy of seeds is likely to be mediated by the chemical composition and the thickness of the seed coat. Here, we investigate the link between the content of phenylpropanoids (i.e., phenolics and flavonoids) present in the chickpea seed coat and dormancy. The relationship between selected phenolic and flavonoid metabolites of chickpea seed coats and dormancy level was assessed using wild and cultivated chickpea parental genotypes and a derived population of recombinant inbred lines (RILs). The selected phenolic and flavonoid metabolites were analyzed via the LC-MS/MS method. Significant differences in the concentration of certain phenolic acids were found among cultivated (Cicer arietinum, ICC4958) and wild chickpea (Cicer reticulatum, PI489777) parental genotypes. These differences were observed in the contents of gallic, caffeic, vanillic, syringic, p-coumaric, salicylic, and sinapic acids, as well as salicylic acid-2-O-ß-d-glucoside and coniferaldehyde. Additionally, significant differences were observed in the flavonoids myricetin, quercetin, luteolin, naringenin, kaempferol, isoorientin, orientin, and isovitexin. When comparing non-dormant and dormant RILs, significant differences were observed in gallic, 3-hydroxybenzoic, syringic, and sinapic acids, as well as the flavonoids quercitrin, quercetin, naringenin, kaempferol, and morin. Phenolic acids were generally more highly concentrated in the wild parental genotype and dormant RILs. We compared the phenylpropanoid content of chickpea seed coats with related legumes, such as pea, lentil, and faba bean. This information could be useful in chickpea breeding programs to reduce dormancy.

TACSTD2 upregulation is an early reaction to lung infection.

TACSTD2 encodes a transmembrane glycoprotein Trop2 commonly overexpressed in carcinomas. While the Trop2 protein was discovered already in 1981 and first antibody-drug conjugate targeting Trop2 were recently approved for cancer therapy, the physiological role of Trop2 is still not fully understood. In this article, we show that TACSTD2/Trop2 expression is evolutionarily conserved in lungs of various vertebrates. By analysis of publicly available transcriptomic data we demonstrate that TACSTD2 level consistently increases in lungs infected with miscellaneous, but mainly viral pathogens. Single cell and subpopulation based transcriptomic data revealed that the major source of TACSTD2 transcript are lung epithelial cells and their progenitors and that TACSTD2 is induced directly in lung epithelial cells following infection. Increase in TACSTD2 expression may represent a mechanism to maintain/restore epithelial barrier function and contribute to regeneration process in infected/damaged lungs.

Expandable Lung Epithelium Differentiated from Human Embryonic Stem Cells.

BACKGROUND: The progenitors to lung airway epithelium that are capable of long-term propagation may represent an attractive source of cells for cell-based therapies, disease modeling, toxicity testing, and others. Principally, there are two main options for obtaining lung epithelial progenitors: (i) direct isolation of endogenous progenitors from human lungs and (ii) in vitro differentiation from some other cell type. The prime candidates for the second approach are pluripotent stem cells, which may provide autologous and/or allogeneic cell resource in clinically relevant quality and quantity. METHODS: By exploiting the differentiation potential of human embryonic stem cells (hESC), here we derived expandable lung epithelium (ELEP) and established culture conditions for their long-term propagation (more than 6 months) in a monolayer culture without a need of 3D culture conditions and/or cell sorting steps, which minimizes potential variability of the outcome. RESULTS: These hESC-derived ELEP express NK2 Homeobox 1 (NKX2.1), a marker of early lung epithelial lineage, display properties of cells in early stages of surfactant production and are able to differentiate to cells exhibitting molecular and morphological characteristics of both respiratory epithelium of airway and alveolar regions. CONCLUSION: Expandable lung epithelium thus offer a stable, convenient, easily scalable and high-yielding cell source for applications in biomedicine.

3D Bioprinted Cardiac Tissues and Devices for Tissue Maturation.

Cardiovascular diseases are the leading cause of mortality worldwide. Given the limited endogenous regenerative capabilities of cardiac tissue, patient-specific anatomy, challenges in treatment options, and shortage of donor tissues for transplantation, there is an urgent need for novel approaches in cardiac tissue repair. 3D bioprinting is a technology based on additive manufacturing which allows for the design of precisely controlled and spatially organized structures, which could possibly lead to solutions in cardiac tissue repair. In this review, we describe the basic morphological and physiological specifics of the heart and cardiac tissues and introduce the readers to the fundamental principles underlying 3D printing technology and some of the materials/approaches which have been used to date for cardiac repair. By summarizing recent progress in 3D printing of cardiac tissue and valves with respect to the key features of cardiovascular tissue (such as contractility, conductivity, and vascularization), we highlight how 3D printing can facilitate surgical planning and provide custom-fit implants and properties that match those from the native heart. Finally, we also discuss the suitability of this technology in the design and fabrication of custom-made devices intended for the maturation of the cardiac tissue, a process that has been shown to increase the viability of implants. Altogether this review shows that 3D printing and bioprinting are versatile and highly modulative technologies with wide applications in cardiac regeneration and beyond.

Building new cardiac vasculature and myocardium: where are we at?

PURPOSE OF REVIEW: This review describes the latest advances in cell therapy, biomaterials and 3D bioprinting for the treatment of cardiovascular disease. RECENT FINDINGS: Cell therapies offer the greatest benefit for patients suffering from chronic ischemic and nonischemic cardiomyopathy. Rather than replacing lost cardiomyocytes, the effects of most cell therapies are mediated by paracrine signalling, mainly through the induction of angiogenesis and immunomodulation. Cell preconditioning, or genetic modifications are being studied to improve the outcomes. Biomaterials offer stand-alone benefits such as bioactive cues for cell survival, proliferation and differentiation, induction of vascularization or prevention of further cardiomyocyte death. They also provide mechanical support or electroconductivity, and can be used to deliver cells, growth factors or drugs to the injured site. Apart from classical biomaterial manufacturing techniques, 3D bioprinting offers greater spatial control over biomaterial deposition and higher resolution of the details, including hollow vessel-like structures. SUMMARY: Cell therapy induces mainly angiogenesis and immunomodulation. The ability to induce direct cardiomyocyte regeneration to replace the lost cardiomyocytes is, however, still missing until embryonic or induced pluripotent stem cell use becomes available. Cell therapy would benefit from combinatorial use with biomaterials, as these can prolong cell retention and survival, offer additional mechanical support and provide inherent bioactive cues. Biomaterials can also be used to deliver growth factors, drugs, and other molecules. 3D bioprinting is a high-resolution technique that has great potential in cardiac therapy.

Delivering More of an Injectable Human Recombinant Collagen III Hydrogel Does Not Improve Its Therapeutic Efficacy for Treating Myocardial Infarction.

Injectable hydrogels are a promising method to enhance repair in the heart after myocardial infarction (MI). However, few studies have compared different strategies for the application of biomaterial treatments. In this study, we use a clinically relevant mouse MI model to assess the therapeutic efficacy of different treatment protocols for intramyocardial injection of a recombinant human collagen III (rHCIII) thermoresponsive hydrogel. Comparing a single hydrogel injection at an early time point (3 h) versus injections at multiple time points (3 h, 1 week, and 2 weeks) post-MI revealed that the single injection group led to superior cardiac function, reduced scar size and inflammation, and increased vascularization. Omitting the 3 h time point and delivering the hydrogel at 1 and 2 weeks post-MI led to poorer cardiac function. The positive effects of the single time point injection (3 h) on scar size and vascular density were lost when the hydrogel's collagen concentration was increased from 1% to 2%, and it did not confer any additional functional improvement. This study shows that early treatment with a rHCIII hydrogel can improve cardiac function post-MI but that injecting more rHCIII (by increased concentration or more over time) can reduce its efficacy, thus highlighting the importance of investigating optimal treatment strategies of biomaterial therapy for MI.

Collagen-Based Microcapsules As Therapeutic Materials for Stem Cell Therapies in Infarcted Myocardium.

As cell therapies emerged, it was quickly realized that pro-regenerative cells directly injected into injured tissue struggled within the inflammatory microenvironment. By using microencapsulation, i.e., encapsulating cells within polymeric biomaterials, they are henceforth protected from the harmful extracellular cues, while still being able to receive oxygen and nutrients and release secreted factors. Previous work showed that stem cells encapsulated within a biologically inert material (agarose) were able to significantly improve the function of the infarcted mouse heart. With the aim of using more bioresponsive microcapsules, we sought to develop an enzymatically degradable, type I collagen-based microcapsule for the intramyocardial delivery of bone marrow-derived mesenchymal stromal cells in a murine model of myocardial infarction.

Multifunctional Nano and Collagen-Based Therapeutic Materials for Skin Repair.

A novel strategy is needed for treating nonhealing wounds, which is able to simultaneously eradicate pathogenic bacteria and promote tissue regeneration. This would improve patient outcome and reduce the number of lower limb amputations. In this work, we present a multifunctional therapeutic approach able to control bacterial infections, provide a protective barrier to a full-thickness wound, and improve wound healing in a clinically relevant animal model. Our approach uses a nanoengineered antimicrobial nanoparticle for creating a sprayable layer onto the wound bed that prevents bacterial proliferation and also eradicates preformed biofilms. As a protective barrier for the wound, we developed a thermoresponsive collagen-based matrix that has prohealing properties and is able to fill wounds independent of their geometries. Our results indicate that using a combination of the matrix with full-thickness microscopic skin tissue columns synergistically contributed to faster and superior skin regeneration in a nonhealing wound model in diabetic mice.

Light-Activated Peptide-Based Materials for Sutureless Wound Closure.

Using chemically modified extracellular matrix proteins, such as collagen, in combination with light for tissue bonding reduces inflammation and minimizes scarring. However, full length animal or recombinant human collagen proteins are difficult to isolate/produce. Thus, short biomimetic collagen peptides with properties equivalent to collagen at both structural and functional levels may be ideal building blocks for the development of remotely triggered adhesives and fillers. In this work, the conjugation of self-assembling collagen-like peptides to acrylate functionalized polyethylene glycol units yielded adhesive filler materials activated by visible light through the incorporation of a photosensitizer. When tested in a murine skin wound model, the photoactivated adhesives showed reduced scar formation and promoted epithelial regeneration.

Injectable human recombinant collagen matrices limit adverse remodeling and improve cardiac function after myocardial infarction.

Despite the success of current therapies for acute myocardial infarction (MI), many patients still develop adverse cardiac remodeling and heart failure. With the growing prevalence of heart failure, a new therapy is needed that can prevent remodeling and support tissue repair. Herein, we report on injectable recombinant human collagen type I (rHCI) and type III (rHCIII) matrices for treating MI. Injecting rHCI or rHCIII matrices in mice during the late proliferative phase post-MI restores the myocardium's mechanical properties and reduces scar size, but only the rHCI matrix maintains remote wall thickness and prevents heart enlargement. rHCI treatment increases cardiomyocyte and capillary numbers in the border zone and the presence of pro-wound healing macrophages in the ischemic area, while reducing the overall recruitment of bone marrow monocytes. Our findings show functional recovery post-MI using rHCI by promoting a healing environment, cardiomyocyte survival, and less pathological remodeling of the myocardium.

Options for modeling the respiratory system: inserts, scaffolds and microfluidic chips.

The human respiratory system is continuously exposed to varying levels of hazardous substances ranging from environmental toxins to purposely administered drugs. If the noxious effects exceed the inherent regenerative capacity of the respiratory system, injured tissue undergoes complex remodeling that can significantly affect lung function and lead to various diseases. Advanced near-to-native in vitro lung models are required to understand the mechanisms involved in pulmonary damage and repair and to reliably test the toxicity of compounds to lung tissue. This review is an overview of the development of in vitro respiratory system models used for study of lung diseases. It includes discussion of using these models for environmental toxin assessment and pulmonary toxicity screening.

A Comprehensive In Vitro Comparison of Preparation Techniques for Fat Grafting.

BACKGROUND: Lipomodeling is a technique that uses the patient's own fat for tissue regeneration and augmentation. The extent of regenerative effect is reported to be determined by the numbers of adipose-derived stem cells and the viability of cells in processed adipose tissue which, together with other factors, influence the degree of graft retention. This study addresses whether differences exist in properties of fat graft obtained by three commonly used techniques. METHODS: Adipose tissue harvested from the hypogastric regions of 14 patients was processed by decantation, centrifugation, and membrane-based tissue filtration. The morphology of each preparation was assessed by electron microscopy and overall cell viability was assessed by live/dead assay. The number of adipose-derived stem cells was determined and their stem cell character was assessed by the presence of cell surface molecules (i.e., CD105, CD90, CD31, and CD45) and by their capacity to differentiate into adipogenic and osteogenic lineages. RESULTS: First, morphologies of processed fat samples obtained by individual procedures differed, but no preparation caused obvious damage to cellular or acellular components. Second, although the highest numbers of adipose-derived stem cells were contained in the upper fraction of centrifuged lipoaspirates, the difference between preparations was marginal. Third, the maximal concentration of adipose fraction (removal of watery component) of lipoaspirate was achieved by membrane-based tissue filtration. Finally, no significant differences in overall viability were detected. CONCLUSIONS: Properties of processed lipoaspirate were influenced by the preparation procedure. However, the differences were not dramatic; both centrifugation and membrane-based filtration are methods of choice whose selection depends on other criteria (e.g., practicality) for individual surgical settings.

Novel electrospun gelatin/oxycellulose nanofibers as a suitable platform for lung disease modeling.

Novel hydrolytically stable gelatin nanofibers modified with sodium or calcium salt of oxycellulose were prepared by electrospinning method. The unique inhibitory effect of these nanofibers against Escherichia coli bacteria was examined by luminometric method. Biocompatibility of these gelatin/oxycellulose nanofibers with eukaryotic cells was tested using human lung adenocarcinoma cell line NCI-H441. Cells firmly adhered to nanofiber surface, as determined by scanning electron microscopy, and no signs of cell dying were detected by fluorescent live/dead assay. We propose that the newly developed gelatin/oxycellulose nanofibers could be used as promising scaffold for lung disease modeling and anti-cancer drug testing.