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Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration

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A special issue of Bioengineering (ISSN 2306-5354). This special issue belongs to the section "Biochemical Engineering".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 34240

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Special Issue Editors

Dr. Ngan F. Huang

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Guest Editor

Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA 94305, USA
Interests: cardiovascular tissue engineering; biomaterials; extracellular matrix interactions; stem cell therapy; peripheral arterial disease; muscle regeneration
Special Issues, Collections and Topics in MDPI journals

Dr. Brandon J. Tefft

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Guest Editor

Medical College of Wisconsin & Marquette University, Department of Biomedical Engineering, Milwaukee, WI 53226, USA
Interests: vascular tissue engineering; heart valve tissue engineering; nanotechnology; cardiovascular regenerative engineering; biomaterials; coronary heart disease; valvular heart disease

Special Issue Information

Dear Colleagues,

It is increasingly appreciated that the extracellular matrix (ECM) provides not only structural support, but also dynamic signaling cues that influence cellular behavior. In the context of tissue engineering and tissue regeneration, the ECM plays a critical role in many aspects, including the regulation of cell survival, cellular reorganization, contractility, as well as in the regulation of engineered cardiovascular tissue formation and function. This issue explores cellular interactions with naturally derived ECMs, biomimetic materials, and synthetic hydrogels. For example, the ECMs can take the form of 3D porous scaffolds, bioinks for 3D bioprinting, or decellularized ECMs. We invite manuscripts that focus on how cell–ECM interactions lead to advances in tissue engineering or in vivo tissue regeneration, as well as in the improved understanding of the underlying molecular biology.

Dr. Ngan F. Huang
Dr. Brandon J. Tefft
Guest Editors

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Keywords

extracellular matrix
tissue engineering
bioprinting
decellularized matrix
tissue regeneration

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Published Papers (11 papers)

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Research

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14 pages, 2570 KiB

Open AccessArticle

Hydrogel Coating Optimization to Augment Engineered Soft Tissue Mechanics in Tissue-Engineered Blood Vessels

by Bryan T. Wonski, Bruce Fisher and Mai T. Lam

Bioengineering 2023, 10(7), 780; https://doi.org/10.3390/bioengineering10070780 - 30 Jun 2023

Cited by 3 | Viewed by 1923

Abstract

Tissue engineering has the advantage of replicating soft tissue mechanics to better simulate and integrate into native soft tissue. However, soft tissue engineering has been fraught with issues of insufficient tissue strength to withstand physiological mechanical requirements. This factor is due to the lack of strength inherent in cell-only constructs and in the biomaterials used for soft tissue engineering and limited extracellular matrix (ECM) production possible in cell culture. To address this issue, we explored the use of an ECM-based hydrogel coating to serve as an adhesive tool, as demonstrated in vascular tissue engineering. The efficacy of cells to supplement mechanical strength in the coating was explored. Specifically, selected coatings were applied to an engineered artery tunica adventitia to accurately test their properties in a natural tissue support structure. Multiple iterations of three primary hydrogels with and without cells were tested: fibrin, collagen, and gelatin hydrogels with and without fibroblasts. The effectiveness of a natural crosslinker to further stabilize and strengthen the hydrogels was investigated, namely genipin extracted from the gardenia fruit. We found that gelatin crosslinked with genipin alone exhibited the highest tensile strength; however, fibrin gel supported cell viability the most. Overall, fibrin gel coating without genipin was deemed optimal for its balance in increasing mechanical strength while still supporting cell viability and was used in the final mechanical and hydrodynamic testing assessments. Engineered vessels coated in fibrin hydrogel with cells resulted in the highest tensile strength of all hydrogel-coated groups after 14 d in culture, demonstrating a tensile strength of 11.9 ± 2.91 kPa, compared to 5.67 ± 1.37 kPa for the next highest collagen hydrogel group. The effect of the fibrin hydrogel coating on burst pressure was tested on our strongest vessels composed of human aortic smooth muscle cells. A significant increase from our previously reported burst pressure of 51.3 ± 2.19 mmHg to 229 ± 23.8 mmHg was observed; however, more work is needed to render these vessels compliant with mechanical and biological criteria for blood vessel substitutes. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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13 pages, 2957 KiB

Open AccessArticle

Fibroblast-Generated Extracellular Matrix Guides Anastomosis during Wound Healing in an Engineered Lymphatic Skin Flap

by Alvis Chiu, Wenkai Jia, Yumeng Sun, Jeremy Goldman and Feng Zhao

Bioengineering 2023, 10(2), 149; https://doi.org/10.3390/bioengineering10020149 - 22 Jan 2023

Viewed by 2608

Abstract

A healthy lymphatic system is required to return excess interstitial fluid back to the venous circulation. However, up to 49% of breast cancer survivors eventually develop breast cancer-related lymphedema due to lymphatic injuries from lymph node dissections or biopsies performed to treat cancer. While early-stage lymphedema can be ameliorated by manual lymph drainage, no cure exists for late-stage lymphedema when lymph vessels become completely dysfunctional. A viable late-stage treatment is the autotransplantation of functional lymphatic vessels. Here we report on a novel engineered lymphatic flap that may eventually replace the skin flaps used in vascularized lymph vessel transfers. The engineered flap mimics the lymphatic and dermal compartments of the skin by guiding multi-layered tissue organization of mesenchymal stem cells and lymphatic endothelial cells with an aligned decellularized fibroblast matrix. The construct was tested in a novel bilayered wound healing model and implanted into athymic nude rats. The in vitro model demonstrated capillary invasion into the wound gaps and deposition of extracellular matrix fibers, which may guide anastomosis and vascular integration of the graft during wound healing. The construct successfully anastomosed in vivo, forming chimeric vessels of human and rat cells. Overall, our flap replacement has high potential for treating lymphedema. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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13 pages, 1937 KiB

Open AccessArticle

Three-Dimensional Bioprinting with Alginate by Freeform Reversible Embedding of Suspended Hydrogels with Tunable Physical Properties and Cell Proliferation

by Yuanjia Zhu, Charles J. Stark, Sarah Madira, Sidarth Ethiraj, Akshay Venkatesh, Shreya Anilkumar, Jinsuh Jung, Seunghyun Lee, Catherine A. Wu, Sabrina K. Walsh, Gabriel A. Stankovich and Yi-Ping Joseph Woo

Bioengineering 2022, 9(12), 807; https://doi.org/10.3390/bioengineering9120807 - 15 Dec 2022

Cited by 14 | Viewed by 3574

Abstract

Extrusion-based three-dimensional (3D) bioprinting is an emerging technology that allows for rapid bio-fabrication of scaffolds with live cells. Alginate is a soft biomaterial that has been studied extensively as a bio-ink to support cell growth in 3D constructs. However, native alginate is a bio-inert material that requires modifications to allow for cell adhesion and cell growth. Cells grown in modified alginates with the RGD (arginine-glycine-aspartate) motif, a naturally existing tripeptide sequence that is crucial to cell adhesion and proliferation, demonstrate enhanced cell adhesion, spreading, and differentiation. Recently, the bioprinting technique using freeform reversible embedding of suspended hydrogels (FRESH) has revolutionized 3D bioprinting, enabling the use of soft bio-inks that would otherwise collapse in air. However, the printability of RGD-modified alginates using the FRESH technique has not been evaluated. The associated physical properties and bioactivity of 3D bio-printed alginates after RGD modification remains unclear. In this study, we characterized the physical properties, printability, and cellular proliferation of native and RGD-modified alginate after extrusion-based 3D bioprinting in FRESH. We demonstrated tunable physical properties of native and RGD-modified alginates after FRESH 3D bioprinting. Sodium alginate with RGD modification, especially at a high concentration, was associated with greatly improved cell viability and integrin clustering, which further enhanced cell proliferation. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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19 pages, 2323 KiB

Open AccessArticle

Keratin Promotes Differentiation of Keratinocytes Seeded on Collagen/Keratin Hydrogels

by Kameel Zuniga, Neda Ghousifam, John Sansalone, Kris Senecal, Mark Van Dyke and Marissa Nichole Rylander

Bioengineering 2022, 9(10), 559; https://doi.org/10.3390/bioengineering9100559 - 15 Oct 2022

Cited by 2 | Viewed by 2744

Abstract

Keratinocytes undergo a complex process of differentiation to form the stratified stratum corneum layer of the skin. In most biomimetic skin models, a 3D hydrogel fabricated out of collagen type I is used to mimic human skin. However, native skin also contains keratin, which makes up 90% of the epidermis and is produced by the keratinocytes present. We hypothesized that the addition of keratin (KTN) in our collagen hydrogel may aid in the process of keratinocyte differentiation compared to a pure collagen hydrogel. Keratinocytes were seeded on top of a 100% collagen or 50/50 C/KTN hydrogel cultured in either calcium-free (Ca-free) or calcium+ (Ca+) media. Our study demonstrates that the addition of keratin and calcium in the media increased lysosomal activity by measuring the glucocerebrosidase (GBA) activity and lysosomal distribution length, an indication of greater keratinocyte differentiation. We also found that the presence of KTN in the hydrogel also increased the expression of involucrin, a differentiation marker, compared to a pure collagen hydrogel. We demonstrate that a combination (i.e., containing both collagen and kerateine or “C/KTN”) hydrogel was able to increase keratinocyte differentiation compared to a pure collagen hydrogel, and the addition of calcium further increased the differentiation of keratinocytes. This multi-protein hydrogel shows promise in future models or treatments to increase keratinocyte differentiation into the stratum corneum. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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14 pages, 3406 KiB

Open AccessArticle

Culturing of Cardiac Fibroblasts in Engineered Heart Matrix Reduces Myofibroblast Differentiation but Maintains Their Response to Cyclic Stretch and Transforming Growth Factor β1

by Meike C. Ploeg, Chantal Munts, Tayeba Seddiqi, Tim J. L. ten Brink, Jonathan Breemhaar, Lorenzo Moroni, Frits. W. Prinzen and Frans. A. van Nieuwenhoven

Bioengineering 2022, 9(10), 551; https://doi.org/10.3390/bioengineering9100551 - 14 Oct 2022

Cited by 5 | Viewed by 2347

Abstract

Isolation and culturing of cardiac fibroblasts (CF) induces rapid differentiation toward a myofibroblast phenotype, which is partly mediated by the high substrate stiffness of the culture plates. In the present study, a 3D model of Engineered Heart Matrix (EHM) of physiological stiffness (Youngs modulus ~15 kPa) was developed using primary adult rat CF and a natural hydrogel collagen type 1 matrix. CF were equally distributed, viable and quiescent for at least 13 days in EHM and the baseline gene expression of myofibroblast-markers alfa-smooth muscle actin (Acta2), and connective tissue growth factor (Ctgf) was significantly lower, compared to CF cultured in 2D monolayers. CF baseline gene expression of transforming growth factor-beta1 (Tgfβ1) and brain natriuretic peptide (Nppb) was higher in EHM-fibers compared to the monolayers. EHM stimulation by 10% cyclic stretch (1 Hz) increased the gene expression of Nppb (3.0-fold), Ctgf (2.1-fold) and Tgfβ1 (2.3-fold) after 24 h. Stimulation of EHM with TGFβ1 (1 ng/mL, 24 h) induced Tgfβ1 (1.6-fold) and Ctgf (1.6-fold). In conclusion, culturing CF in EHM of physiological stiffness reduced myofibroblast marker gene expression, while the CF response to stretch or TGFβ1 was maintained, indicating that our novel EHM structure provides a good physiological model to study CF function and myofibroblast differentiation. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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16 pages, 22378 KiB

Open AccessArticle

Human-Origin iPSC-Based Recellularization of Decellularized Whole Rat Livers

by Aylin Acun, Ruben Oganesyan, Maria Jaramillo, Martin L. Yarmush and Basak E. Uygun

Bioengineering 2022, 9(5), 219; https://doi.org/10.3390/bioengineering9050219 - 19 May 2022

Cited by 12 | Viewed by 3333

Abstract

End-stage liver diseases lead to mortality of millions of patients, as the only treatment available is liver transplantation and donor scarcity means that patients have to wait long periods before receiving a new liver. In order to minimize donor organ scarcity, a promising bioengineering approach is to decellularize livers that do not qualify for transplantation. Through decellularization, these organs can be used as scaffolds for developing new functional organs. In this process, the original cells of the organ are removed and ideally should be replaced by patient-specific cells to eliminate the risk of immune rejection. Induced pluripotent stem cells (iPSCs) are ideal candidates for developing patient-specific organs, yet the maturity and functionality of iPSC-derived cells do not match those of primary cells. In this study, we introduced iPSCs into decellularized rat liver scaffolds prior to the start of differentiation into hepatic lineages to maximize the exposure of iPSCs to native liver matrices. Through exposure to the unique composition and native 3D organization of the liver microenvironment, as well as the more efficient perfusion culture throughout the differentiation process, iPSC differentiation into hepatocyte-like cells was enhanced. The resulting cells showed significantly higher expression of mature hepatocyte markers, including important CYP450 enzymes, along with lower expression of fetal markers, such as AFP. Importantly, the gene expression profile throughout the different stages of differentiation was more similar to native development. Our study shows that the native 3D liver microenvironment has a pivotal role to play in the development of human-origin hepatocyte-like cells with more mature characteristics. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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Review

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35 pages, 2969 KiB

Open AccessReview

Engineering Cell–ECM–Material Interactions for Musculoskeletal Regeneration

by Calvin L. Jones, Brian T. Penney and Sophia K. Theodossiou

Bioengineering 2023, 10(4), 453; https://doi.org/10.3390/bioengineering10040453 - 7 Apr 2023

Cited by 7 | Viewed by 2746

Abstract

The extracellular microenvironment regulates many of the mechanical and biochemical cues that direct musculoskeletal development and are involved in musculoskeletal disease. The extracellular matrix (ECM) is a main component of this microenvironment. Tissue engineered approaches towards regenerating muscle, cartilage, tendon, and bone target the ECM because it supplies critical signals for regenerating musculoskeletal tissues. Engineered ECM–material scaffolds that mimic key mechanical and biochemical components of the ECM are of particular interest in musculoskeletal tissue engineering. Such materials are biocompatible, can be fabricated to have desirable mechanical and biochemical properties, and can be further chemically or genetically modified to support cell differentiation or halt degenerative disease progression. In this review, we survey how engineered approaches using natural and ECM-derived materials and scaffold systems can harness the unique characteristics of the ECM to support musculoskeletal tissue regeneration, with a focus on skeletal muscle, cartilage, tendon, and bone. We summarize the strengths of current approaches and look towards a future of materials and culture systems with engineered and highly tailored cell–ECM–material interactions to drive musculoskeletal tissue restoration. The works highlighted in this review strongly support the continued exploration of ECM and other engineered materials as tools to control cell fate and make large-scale musculoskeletal regeneration a reality. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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16 pages, 928 KiB

Open AccessReview

Anti-Inflammatory and Anti-Thrombogenic Properties of Arterial Elastic Laminae

by Jeremy Goldman, Shu Q. Liu and Brandon J. Tefft

Bioengineering 2023, 10(4), 424; https://doi.org/10.3390/bioengineering10040424 - 28 Mar 2023

Cited by 2 | Viewed by 2117

Abstract

Elastic laminae, an elastin-based, layered extracellular matrix structure in the media of arteries, can inhibit leukocyte adhesion and vascular smooth muscle cell proliferation and migration, exhibiting anti-inflammatory and anti-thrombogenic properties. These properties prevent inflammatory and thrombogenic activities in the arterial media, constituting a mechanism for the maintenance of the structural integrity of the arterial wall in vascular disorders. The biological basis for these properties is the elastin-induced activation of inhibitory signaling pathways, involving the inhibitory cell receptor signal regulatory protein α (SIRPα) and Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1). The activation of these molecules causes deactivation of cell adhesion- and proliferation-regulatory signaling mechanisms. Given such anti-inflammatory and anti-thrombogenic properties, elastic laminae and elastin-based materials have potential for use in vascular reconstruction. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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15 pages, 2010 KiB

Open AccessReview

Extracellular Vesicles as Regulators of the Extracellular Matrix

by Neil J. Patel, Anisa Ashraf and Eun Ji Chung

Bioengineering 2023, 10(2), 136; https://doi.org/10.3390/bioengineering10020136 - 19 Jan 2023

Cited by 24 | Viewed by 4081

Abstract

Extracellular vesicles (EVs) are small membrane-bound vesicles secreted into the extracellular space by all cell types. EVs transfer their cargo which includes nucleic acids, proteins, and lipids to facilitate cell-to-cell communication. As EVs are released and move from parent to recipient cell, EVs interact with the extracellular matrix (ECM) which acts as a physical scaffold for the organization and function of cells. Recent work has shown that EVs can modulate and act as regulators of the ECM. This review will first discuss EV biogenesis and the mechanism by which EVs are transported through the ECM. Additionally, we discuss how EVs contribute as structural components of the matrix and as components that aid in the degradation of the ECM. Lastly, the role of EVs in influencing recipient cells to remodel the ECM in both pathological and therapeutic contexts is examined. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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26 pages, 1733 KiB

Open AccessReview

Engineering Spatiotemporal Control in Vascularized Tissues

by Astha Khanna, Beu P. Oropeza and Ngan F. Huang

Bioengineering 2022, 9(10), 555; https://doi.org/10.3390/bioengineering9100555 - 14 Oct 2022

Cited by 9 | Viewed by 3575

Abstract

A major challenge in engineering scalable three-dimensional tissues is the generation of a functional and developed microvascular network for adequate perfusion of oxygen and growth factors. Current biological approaches to creating vascularized tissues include the use of vascular cells, soluble factors, and instructive biomaterials. Angiogenesis and the subsequent generation of a functional vascular bed within engineered tissues has gained attention and is actively being studied through combinations of physical and chemical signals, specifically through the presentation of topographical growth factor signals. The spatiotemporal control of angiogenic signals can generate vascular networks in large and dense engineered tissues. This review highlights the developments and studies in the spatiotemporal control of these biological approaches through the coordinated orchestration of angiogenic factors, differentiation of vascular cells, and microfabrication of complex vascular networks. Fabrication strategies to achieve spatiotemporal control of vascularization involves the incorporation or encapsulation of growth factors, topographical engineering approaches, and 3D bioprinting techniques. In this article, we highlight the vascularization of engineered tissues, with a focus on vascularized cardiac patches that are clinically scalable for myocardial repair. Finally, we discuss the present challenges for successful clinical translation of engineered tissues and biomaterials. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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15 pages, 1038 KiB

Open AccessReview

Engineering Smooth Muscle to Understand Extracellular Matrix Remodeling and Vascular Disease

by Danielle Yarbrough and Sharon Gerecht

Bioengineering 2022, 9(9), 449; https://doi.org/10.3390/bioengineering9090449 - 7 Sep 2022

Cited by 5 | Viewed by 3134

Abstract

The vascular smooth muscle is vital for regulating blood pressure and maintaining cardiovascular health, and the resident smooth muscle cells (SMCs) in blood vessel walls rely on specific mechanical and biochemical signals to carry out these functions. Any slight change in their surrounding environment causes swift changes in their phenotype and secretory profile, leading to changes in the structure and functionality of vessel walls that cause pathological conditions. To adequately treat vascular diseases, it is essential to understand how SMCs crosstalk with their surrounding extracellular matrix (ECM). Here, we summarize in vivo and traditional in vitro studies of pathological vessel wall remodeling due to the SMC phenotype and, conversely, the SMC behavior in response to key ECM properties. We then analyze how three-dimensional tissue engineering approaches provide opportunities to model SMCs’ response to specific stimuli in the human body. Additionally, we review how applying biomechanical forces and biochemical stimulation, such as pulsatile fluid flow and secreted factors from other cell types, allows us to study disease mechanisms. Overall, we propose that in vitro tissue engineering of human vascular smooth muscle can facilitate a better understanding of relevant cardiovascular diseases using high throughput experiments, thus potentially leading to therapeutics or treatments to be tested in the future. Full article

(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)

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