The past 20 years have witnessed ever-growing evidence that the mechanical properties of biological tissues, from nanoscale to macroscale dimensions, are fundamental for cellular behaviour and consequent tissue functionality. This knowledge, combined with previously known biochemical cues, has greatly advanced the field of biomaterial development, tissue engineering and regenerative medicine. It is now established that approaches to engineer biological tissues must integrate and approximate the mechanics, both static and dynamic, of native tissues. Nevertheless, the literature on the mechanical properties of biological tissues differs greatly in methodology, and the available data are widely dispersed. This Review gathers together the most important data on the stiffness of living tissues and discusses the intricacies of tissue stiffness from a materials perspective, highlighting the main challenges associated with engineering lifelike tissues and proposing a unified view of this as yet unreported topic. Emerging advances that might pave the way for the next decade’s take on bioengineered tissue stiffness are also presented, and differences and similarities between tissues in health and disease are discussed, along with various techniques for characterizing tissue stiffness at various dimensions from individual cells to organs. The complexity of biological tissue presents a challenge for engineering of mechanically compatible materials. In this Review, the stiffness of tissue components — from extracellular matrix and single cells to bulk tissue — is outlined, and how this understanding facilitates the engineering of materials with lifelike properties is discussed.

/pdf/the-stiffness-of-living-tissues-and-its-implications-for-49xikp5kk1.pdf

The stiffness of living tissues and its implications for tissue engineering

Tissue engineering and regenerative medicine involve many different artificial and biologic materials, frequently integrated in composite scaffolds, which can be repopulated with various cell types. One of the most promising scaffolds is decellularized allogeneic extracellular matrix (ECM) then recellularized by autologous or stem cells, in order to develop fully personalized clinical approaches. Decellularization protocols have to efficiently remove immunogenic cellular materials, maintaining the nonimmunogenic ECM, which is endowed with specific inductive/differentiating actions due to its architecture and bioactive factors. In the present paper, we review the available literature about the development of grafts from decellularized human tissues/organs. Human tissues may be obtained not only from surgery but also from cadavers, suggesting possible development of Human Tissue BioBanks from body donation programs. Many human tissues/organs have been decellularized for tissue engineering purposes, such as cartilage, bone, skeletal muscle, tendons, adipose tissue, heart, vessels, lung, dental pulp, intestine, liver, pancreas, kidney, gonads, uterus, childbirth products, cornea, and peripheral nerves. In vitro recellularizations have been reported with various cell types and procedures (seeding, injection, and perfusion). Conversely, studies about in vivo behaviour are poorly represented. Actually, the future challenge will be the development of human grafts to be implanted fully restored in all their structural/functional aspects.

https://www.mdpi.com/1422-0067/19/12/4117/pdf

Tissue-Engineered Grafts from Human Decellularized Extracellular Matrices: A Systematic Review and Future Perspectives

Engineered heart tissue models from hiPSC-derived cardiomyocytes and cardiac ECM for disease modeling and drug testing applications.

Connective tissue is one of the four major types of animal tissue and plays essential roles throughout the human body. Genetic factors, aging, and trauma all contribute to connective tissue dysfunction and motivate the need for strategies to promote healing and regeneration. The goal here is to link a fundamental understanding of connective tissues and their multiscale properties to better inform the design and translation of novel biomaterials to promote their regeneration. Major clinical problems in adipose tissue, cartilage, dermis, and tendon are discussed that inspire the need to replace native connective tissue with biomaterials. Then, multiscale structure-function relationships in native soft connective tissues that may be used to guide material design are detailed. Several biomaterials strategies to improve healing of these tissues that incorporate biologics and are biologic-free are reviewed. Finally, important guidance documents and standards (ASTM, FDA, and EMA) that are important to consider for translating new biomaterials into clinical practice are highligted.

Biomaterials to Mimic and Heal Connective Tissues.

Adipose-derived stromal cells mediate in vivo adipogenesis, angiogenesis and inflammation in decellularized adipose tissue bioscaffolds.

Characterization and assessment of hyperelastic and elastic properties of decellularized human adipose tissues.

To more closely mimic the native cellular microenvironment, 3D scaffolds derived from the extracellular matrix (ECM) are being developed as alternatives to conventional 2D culture systems. In the present study, we established methods to fabricate nonchemically cross-linked 3D porous foams derived entirely from decellularized porcine left ventricle (DLV) for use as an in vitro cardiac cell culture platform. Furthermore, we explored the effects of physically preprocessing the DLV through mechanical mincing versus cryomilling, as well as varying the ECM concentration on the structure, composition, and physical properties of the foams. Our results indicate that the less highly processed minced foams had a more cohesive and complex network of ECM components, enhanced mechanical properties, and improved stability under simulated culturing conditions. To validate the DLV foams, a proof-of-concept study was conducted to explore the early cardiomyogenic differentiation of pericardial fat adipose-derived stem/stromal cells (pfASCs) on the minced DLV foams relative to purified collagen I gel controls. Differentiation was induced using a modified cardiomyogenic medium (MCM) or through stimulation with 5-azacytidine (5-aza), and cardiomyocyte marker expression was characterized by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction. Our results indicate that early markers of cardiomyogenic differentiation were significantly enhanced on the DLV foams cultured in MCM, suggesting a synergistic effect of the cardiac ECM-derived scaffolds and the culture medium on the induction of pfASC differentiation. Furthermore, in analyzing the response in the noninduced control groups, the foams were observed to provide a mildly inductive microenvironment for pfASC cardiomyogenesis, supporting the rationale for using tissue-specific ECM as a substrate for cardiac cell culture applications.

Porous, Ventricular Extracellular Matrix-Derived Foams as a Platform for Cardiac Cell Culture

Developing suitable biomaterials for post-mastectomy or post-lumpectomy breast reconstruction is highly important. This study is aimed at evaluating biomechanical suitability of decellularized adipose tissue (DAT) for this purpose. The study involves computational experiments for evaluating deformation of the breast reconstructed using DAT under loading conditions pertaining to two common body position changes of prone-to-supine and prone-to-upright. This was conducted using nonlinear finite element models where the breast geometry was obtained from MRI image of a female breast. The experiments were performed using DAT sourced from various adipose tissue depots in comparison to natural adipose tissue. Data obtained from the conducted experiments showed no contour defects with various DAT materials for simulated post-mastectomy or post-lumpectomy breast reconstruction under the loading conditions. They also demonstrated that a breast reconstructed using DAT derived from the breast or subcutaneous abdominal depots exhibit significantly closer deformation, both qualitatively and quantitatively, to that of a normal breast under the same loading conditions. Similarity of DAT deformation to that of natural breast tissue in post-surgery breast reconstruction was assessed using nonlinear finite element analysis. Our results provide evidence that DAT derived from subcutaneous abdominal and breast depots yield more analogous deformation pattern to the natural tissue in post-mastectomy breast reconstruction applications. This is quite encouraging, as breast and subcutaneous adipose tissue can be readily obtained in large quantities from breast or abdominal lipo-reduction surgery procedures. Furthermore, in post-lumpectomy cases all DAT samples used in this research showed similar deformation, and thus are suitable as breast tissue substituents.

Comparative biomechanical study of using decellularized human adipose tissues for post-mastectomy and post-lumpectomy breast reconstruction.

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Characterization and assessment of hyperelastic and elastic properties of decellularized human adipose tissues.

Porous, Ventricular Extracellular Matrix-Derived Foams as a Platform for Cardiac Cell Culture

Comparative biomechanical study of using decellularized human adipose tissues for post-mastectomy and post-lumpectomy breast reconstruction.