scholarly journals TISSUE ENGINEERING: FROM RESEARCH TO CLINICAL APPLICATION IN REGENERATIVE MEDICINE

1970 ◽  
pp. 159-192
Author(s):  
Enrico Tognana ◽  
Lanfranco Callegaro
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Hyaluronic Acid ◽  
Regenerative Medicine ◽  
Therapeutic Option ◽  
Cartilage Tissue ◽  
Sequence Of Events ◽  
Benzyl Esters ◽  
Tissue Restoration

Tissue engineering strategies have recently emerged as the most advanced therapeutic option presently available in regenerative medicine. Tissue engineering encompasses the use of cells and their molecules in artificial constructs that compensate for lost or impaired body functions. It is based upon scaffoldguided tissue regeneration and involves the seeding of porous, biodegradable scaffolds with donor cells, which become differentiated and mimic naturally occurring tissues. These tissue-engineered constructs are then implanted into the patient to replace diseased or damaged tissues. Our approach to regenerative medicine is based on hyaluronan derivative polymers. HYAFF® is a class of hyaluronan derivative polymers obtained by coupling reaction. The strategy behind the creation of these polymers was to improve the stability of the polymer by esterifying the free carboxyl group of glucuronic acid, frequently repeated along the hyaluronic acid chain, with different types of alcohols. Once esterification of the polymer has been obtained, the material can easily be processed to produce membranes, fibres, sponges, microspheres and other devices, by extrusion, lyophilization or spray drying. A broad variety of polymers can be subsequently generated either by changing the type of ester group introduced or the extent of the esterification. The benzyl esters of hyaluronan, termed HYAFF®-11, are one of the most characterized HYAFF® polymers, from both the physicochemical and biological viewpoints, produced starting from hyaluronan of about 200 KDa. The ideal scaffold for tissue engineering should provide an immediate support to cells and have mechanical properties matching those of the tissue being repaired. Gradually then the material should be resorbed, as the cells begin secreting their own extracellular matrix, thus allowing for an optimal integration between newformed and existing tissue. Extensive biocompatibility studies have demonstrated the safety of HYAFF® scaffolds and their ability to be resorbed in the absence of an inflammatory response. Moreover, when implanted tend to promote the recapitulation of the events that facilitate tissue repair. HYAFF®-11 three-dimensional matrices support the in vitro growth of highly viable chondrocytes and fibroblasts. Similarly, micro-perforated membrane supports the growth and differentiation of keratinocytes. These cells, previously expanded on plastic and hence seeded into the HYAFF® scaffold, produce a characteristic extracellular matrix rich in proteoglycans expressing the typical markers of the tissues of their origin. Hyaluronan presents a variety of multi-functional activity being both a structural and informational molecule. Investigation of hyaluronan synthesis and degradation, the identification of new receptors and binding proteins and the elucidation of hyaluronan-dependent signaling pathways keep providing novel insights into the true biological functions of this intriguing polymer. The possibility to elaborate this natural polymer in different physical forms, as HYAFF® biopolymers family is allowing to do, has given the opportunity to translate tissue engineering strategies in clinical practice providing a biomaterial that induces and modulates the sequence of events that lead to damage tissue restoration. The following chapter will report how tissue engineering approach and hyaluronic acid technology could improve the biological function of cell transplantation in the treatment of tissue defects, in particular for skin and cartilage tissue restoration.

Dynamic hyaluronic acid hydrogel with covalent linked gelatin as an anti-oxidative bioink for cartilage tissue engineering

2021 ◽  
Author(s):  
Wen Shi ◽  
Fang Fang ◽  
Yunfan Kong ◽  
Sydney E Greer ◽  
Mitchell A Kuss ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Hyaluronic Acid ◽  
Therapeutic Option ◽  
Phenylboronic Acid ◽  
Cartilage Tissue Engineering ◽  
Covalent Bond ◽  
Cartilage Tissue ◽  
Poly Vinyl Alcohol ◽  
Extracellular Matrix Components

Abstract Cartilage tissue engineering has arisen as a promising therapeutic option for degenerative joint diseases, such as osteoarthritis, in the hope of restoring the structure and physiological functions. Hydrogels are promising biomaterials for developing engineered constructs for cartilage regeneration. However, such cell-laden constructs could be exposed to elevated levels of reactive oxygen species (ROS) in the inflammatory microenvironment after being implanted into injured joints, which may affect their phenotype and normal functions and thereby hinder the regeneration efficacy. To attenuate ROS induced side effects, a multifunctional hydrogel with an innate anti-oxidative ability was produced in this study. The hydrogel was rapidly formed through a dynamic covalent bond between phenylboronic acid grafted hyaluronic acid (HA-PBA) and poly (vinyl alcohol) (PVA) and was further stabilized through a secondary crosslinking between the acrylate moiety on HA-PBA and the free thiol group from thiolated gelatin. The hydrogel is cyto-compatible and injectable and can be used as a bioink for 3D bioprinting. The viscoelastic properties of the hydrogels could be modulated through the hydrogel precursor concentration. The presence of dynamic covalent linkages contributed to its shear-thinning property and thus good printability of the hydrogel, resulting in the fabrication of a porous grid construct and a meniscus like scaffold at high structural fidelity. The bioprinted hydrogel promoted cell adhesion and chondrogenic differentiation of encapsulated rabbit adipose derived mesenchymal stem cells. Meanwhile, the hydrogel supported robust deposition of extracellular matrix components, including glycosaminoglycans and type II collagen, by embedded mouse chondrocytes in vitro. Most importantly, the hydrogel could protect encapsulated chondrocytes from ROS induced downregulation of cartilage-specific anabolic genes (ACAN and COL2) and upregulation of a catabolic gene (MMP13) after incubation with H2O2. Furthermore, intra-articular injection of the hydrogel in mice revealed adequate stability and good biocompatibility in vivo. These results demonstrate that this hydrogel can be used as a novel bioink for the generation of 3D bioprinted constructs with anti-ROS ability to potentially enhance cartilage tissue regeneration in a chronic inflammatory and elevated ROS microenvironment.

scholarly journals A biomimetic extracellular matrix for cartilage tissue engineering centered on photocurable gelatin, hyaluronic acid and chondroitin sulfate

2014 ◽  
Vol 10 (1) ◽  
pp. 214-223 ◽  
Author(s):  
Peter A. Levett ◽  
Ferry P.W. Melchels ◽  
Karsten Schrobback ◽  
Dietmar W. Hutmacher ◽  
Jos Malda ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Hyaluronic Acid ◽  
Chondroitin Sulfate ◽  
Cartilage Tissue Engineering ◽  
Cartilage Tissue

Influence of Chondrocyte Zone on Co-Cultures With Mesenchymal Stem Cells in HA Hydrogels for Cartilage Tissue Engineering

2012 ◽  
Author(s):  
Minwook Kim ◽  
Jason A. Burdick ◽  
Robert L. Mauck
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hyaluronic Acid ◽  
Articular Chondrocytes ◽  
Cartilage Tissue Engineering ◽  
3D Culture ◽  
Cartilage Tissue ◽  
Cell Type

Mesenchymal stem cells (MSCs) are an attractive cell type for cartilage tissue engineering in that they can undergo chondrogenesis in a variety of 3D contexts [1]. Focused efforts in MSC-based cartilage tissue engineering have recently culminated in the formation of biologic materials possessing biochemical and functional mechanical properties that match that of the native tissue [2]. These approaches generally involve the continuous or intermittent application of pro-chondrogenic growth factors during in vitro culture. For example, in one recent study, we showed robust construct maturation in MSC-seeded hyaluronic acid (HA) hydrogels transiently exposed to high levels of TGF-β3 [3]. Despite the promise of this approach, MSCs are a multipotent cell type and retain a predilection towards hypertrophic phenotypic conversion (i.e., bone formation) when removed from a pro-chondrogenic environment (e.g., in vivo implantation). Indeed, even in a chondrogenic environment, many MSC-based cultures express pre-hypertrophic markers, including type X collagen, MMP13, and alkaline phosphatase [4]. To address this issue, recent studies have investigated co-culture of human articular chondrocytes and MSCs in both pellet and hydrogel environments. Chondrocytes appear to enhance the initial efficiency of MSC chondrogenic conversion, as well as limit hypertrophic changes in some instances (potentially via secretion of PTHrP and/or other factors) [5–7]. While these findings are intriguing, articular cartilage has a unique depth-dependent morphology including zonal differences in chondrocyte identity. Ng et al. showed that zonal chondrocytes seeded in a bi-layered agarose hydrogel construct can recreate depth-dependent cellular and mechanical heterogeneity, suggesting that these identities are retained with transfer to 3D culture systems [8]. Further, Cheng et al. showed that differences in matrix accumulation and hypertrophy in zonal chondrocytes was controlled by bone morphogenic protein [9]. To determine whether differences in zonal chondrocyte identity influences MSC fate decisions, we evaluated functional properties and phenotypic stability in photocrosslinked hyaluronic acid (HA) hydrogels using distinct, zonal chondrocyte cell fractions co-cultured with bone marrow derived MSCs.

scholarly journals A Rapid Crosslinkable Maleimide-Modified Hyaluronic Acid and Gelatin Hydrogel Delivery System for Regenerative Applications

Gels ◽  
2021 ◽  
Vol 7 (1) ◽  
pp. 13
Author(s):  
Kyung Min Yoo ◽  
Sean V. Murphy ◽  
Aleksander Skardal
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Hyaluronic Acid ◽  
Regenerative Medicine ◽  
Cell Encapsulation ◽  
Dermal Fibroblasts ◽  
Size Exclusion ◽  
Proton Nuclear Magnetic Resonance ◽  
Functional Requirements ◽  
Exclusion Chromatography

Hydrogels have played a significant role in many applications of regenerative medicine and tissue engineering due to their versatile properties in realizing design and functional requirements. However, as bioengineered solutions are translated towards clinical application, new hurdles and subsequent material requirements can arise. For example, in applications such as cell encapsulation, drug delivery, and biofabrication, in a clinical setting, hydrogels benefit from being comprised of natural extracellular matrix-based materials, but with defined, controllable, and modular properties. Advantages for these clinical applications include ultraviolet light-free and rapid polymerization crosslinking kinetics, and a cell-friendly crosslinking environment that supports cell encapsulation or in situ crosslinking in the presence of cells and tissue. Here we describe the synthesis and characterization of maleimide-modified hyaluronic acid (HA) and gelatin, which are crosslinked using a bifunctional thiolated polyethylene glycol (PEG) crosslinker. Synthesized products were evaluated by proton nuclear magnetic resonance (NMR), ultraviolet visibility spectrometry, size exclusion chromatography, and pH sensitivity, which confirmed successful HA and gelatin modification, molecular weights, and readiness for crosslinking. Gelation testing both by visual and NMR confirmed successful and rapid crosslinking, after which the hydrogels were characterized by rheology, swelling assays, protein release, and barrier function against dextran diffusion. Lastly, biocompatibility was assessed in the presence of human dermal fibroblasts and keratinocytes, showing continued proliferation with or without the hydrogel. These initial studies present a defined, and well-characterized extracellular matrix (ECM)-based hydrogel platform with versatile properties suitable for a variety of applications in regenerative medicine and tissue engineering.

scholarly journals Extracellular Matrix-Based Biomaterials for Cardiovascular Tissue Engineering

2021 ◽  
Vol 8 (11) ◽  
pp. 137
Author(s):  
Astha Khanna ◽  
Maedeh Zamani ◽  
Ngan F. Huang
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Regenerative Medicine ◽  
Three Dimensional ◽  
Vascular Differentiation ◽  
Cardiovascular Tissue ◽  
Cellular Behavior ◽  
Cardiovascular Tissue Engineering ◽  
And Function

Regenerative medicine and tissue engineering strategies have made remarkable progress in remodeling, replacing, and regenerating damaged cardiovascular tissues. The design of three-dimensional (3D) scaffolds with appropriate biochemical and mechanical characteristics is critical for engineering tissue-engineered replacements. The extracellular matrix (ECM) is a dynamic scaffolding structure characterized by tissue-specific biochemical, biophysical, and mechanical properties that modulates cellular behavior and activates highly regulated signaling pathways. In light of technological advancements, biomaterial-based scaffolds have been developed that better mimic physiological ECM properties, provide signaling cues that modulate cellular behavior, and form functional tissues and organs. In this review, we summarize the in vitro, pre-clinical, and clinical research models that have been employed in the design of ECM-based biomaterials for cardiovascular regenerative medicine. We highlight the research advancements in the incorporation of ECM components into biomaterial-based scaffolds, the engineering of increasingly complex structures using biofabrication and spatial patterning techniques, the regulation of ECMs on vascular differentiation and function, and the translation of ECM-based scaffolds for vascular graft applications. Finally, we discuss the challenges, future perspectives, and directions in the design of next-generation ECM-based biomaterials for cardiovascular tissue engineering and clinical translation.

scholarly journals In Vitro Generation of Novel Functionalized Biomaterials for Use in Oral and Dental Regenerative Medicine Applications

Materials ◽  
2020 ◽  
Vol 13 (7) ◽  
pp. 1692 ◽  
Author(s):  
Cristina Blanco-Elices ◽  
Enrique España-Guerrero ◽  
Miguel Mateu-Sanz ◽  
David Sánchez-Porras ◽  
Óscar García-García ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Regenerative Medicine ◽  
Oral Mucosa ◽  
Dental Tissues ◽  
Extracellular Matrix Components ◽  
Matrix Components ◽  
Time Required ◽  
Vitro Development

Recent advances in tissue engineering offer innovative clinical alternatives in dentistry and regenerative medicine. Tissue engineering combines human cells with compatible biomaterials to induce tissue regeneration. Shortening the fabrication time of biomaterials used in tissue engineering will contribute to treatment improvement, and biomaterial functionalization can be exploited to enhance scaffold properties. In this work, we have tested an alternative biofabrication method by directly including human oral mucosa tissue explants within the biomaterial for the generation of human bioengineered mouth and dental tissues for use in tissue engineering. To achieve this, acellular fibrin–agarose scaffolds (AFAS), non-functionalized fibrin-agarose oral mucosa stroma substitutes (n-FAOM), and novel functionalized fibrin-agarose oral mucosa stroma substitutes (F-FAOM) were developed and analyzed after 1, 2, and 3 weeks of in vitro development to determine extracellular matrix components as compared to native oral mucosa controls by using histochemistry and immunohistochemistry. Results demonstrate that functionalization speeds up the biofabrication method and contributes to improve the biomimetic characteristics of the scaffold in terms of extracellular matrix components and reduce the time required for in vitro tissue development.

scholarly journals Cell-derived Extracellular Matrix as maintaining Biomaterial for adipogenic differentiation

2020 ◽  
Vol 6 (3) ◽  
pp. 410-413
Author(s):  
Petra J. Kluger ◽  
Svenja Nellinger ◽  
Simon Heine ◽  
Ann-Cathrin Volz
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Adipogenic Differentiation ◽  
Cellular Activity ◽  
Adipose Tissue Engineering ◽  
Physical Support ◽  
Supporting Effect ◽  
Brdu Assay ◽  
The Impact

AbstractThe extracellular matrix (ECM) naturally surrounds cells in humans, and therefore represents the ideal biomaterial for tissue engineering. ECM from different tissues exhibit different composition and physical characteristics. Thus, ECM provides not only physical support but also contains crucial biochemical signals that influence cell adhesion, morphology, proliferation and differentiation. Next to native ECM from mature tissue, ECM can also be obtained from the in vitro culture of cells. In this study, we aimed to highlight the supporting effect of cell-derived- ECM (cdECM) on adipogenic differentiation. ASCs were seeded on top of cdECM from ASCs (scdECM) or pre-adipocytes (acdECM). The impact of ECM on cellular activity was determined by LDH assay, WST I assay and BrdU assay. A supporting effect of cdECM substrates on adipogenic differentiation was determined by oil red O staining and subsequent quantification. Results revealed no effect of cdECM substrates on cellular activity. Regarding adipogenic differentiation a supporting effect of cdECM substrates was obtained compared to control. With these results, we confirm cdECM as a promising biomaterial for adipose tissue engineering.

scholarly journals Recapitulating Cardiac Structure and Function In Vitro from Simple to Complex Engineering

Micromachines ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 386
Author(s):  
Ana Santos ◽  
Yongjun Jang ◽  
Inwoo Son ◽  
Jongseong Kim ◽  
Yongdoo Park
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Computational Modeling ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Cells

Cardiac tissue engineering aims to generate in vivo-like functional tissue for the study of cardiac development, homeostasis, and regeneration. Since the heart is composed of various types of cells and extracellular matrix with a specific microenvironment, the fabrication of cardiac tissue in vitro requires integrating technologies of cardiac cells, biomaterials, fabrication, and computational modeling to model the complexity of heart tissue. Here, we review the recent progress of engineering techniques from simple to complex for fabricating matured cardiac tissue in vitro. Advancements in cardiomyocytes, extracellular matrix, geometry, and computational modeling will be discussed based on a technology perspective and their use for preparation of functional cardiac tissue. Since the heart is a very complex system at multiscale levels, an understanding of each technique and their interactions would be highly beneficial to the development of a fully functional heart in cardiac tissue engineering.

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