Tendon Differentiation on Decellularized Extracellular Matrix Under Cyclic Loading.

Engineering Biomimetic Culture Systems: Impact On Human Bone Marrow-Derived Stem Cells.

Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow and shear stress. Significant variations in mechanical forces, of physiological or physiopathological nature, occur in vivo. These are accompanied by phenotypical modulation of smooth muscle cells and endothelial cells, producing structural modifications of the arterial wall. In all the cases, vascular remodelling can be allotted to a modification of the tensional strain or shear, and underlie a trend to reestablish baseline mechanical conditions. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Mechanical forces also initiate complex signal transduction cascades, including nuclear factor-kappaB and mitogen-activated protein kinase pathways, leading to functional changes within the cell.

The bone remodeling cycle is intimately involved in the metabolic homeostasis of mineral balance.1 Bone formation and the remodeling cycle are essential in maintaining the structural integrity of skeletal tissue in response to the mechanical loading to which it is subjected.2, 3 It is likely that remodeling also provides the means of repairing bone tissue damaged as a result of mechanical fatigue.4 Thus, the skeletal cells (osteoblasts and osteoclasts) that mediate the remodeling process almost certainly are regulated by their mechanical environment. In the article by Terai et al., "Role of osteopontin in bone remodeling caused by mechanical stress"5 published in this issue of JBMR, data are presented that begin to elucidate the molecular events that regulate the remodeling cycle in response to mechanical stimulation. The authors show that induction of osteopontin (OPN) expression by osteoblasts in response to mechanical stimulation provides one of the mechanisms by which osteoclast function is coupled to a response that is regulated by the mechanical loading of the bone tissue. A brief review is presented in this perspective on the state of knowledge concerning the function of OPN in bone and other tissues. This perspective also presents the emerging picture that OPN in particular, as well as other molecules of the extracellular matrix (ECM), play essential roles in skeletal tissue structure and also mediate crucial autocrine and paracrine functions in the regulation of tissue formation and remodeling. OPN was initially characterized as one of the predominant noncollagenous proteins that accumulate in the ECM of bone tissue.6-10 Both its levels of expression relative to other noncollagenous proteins,11, 12 and its quantities of accumulation6-10, 13, 14 in the bone demonstrate that it's one of the most prevalent noncollagenous proteins synthesized by osteoblasts. The protein is ∼300 amino acids in length and shows a variable size on SDS-PAGE (∼70–45 kDa) due primarily to its differing degrees of post-translational modifications. Sequence comparisons among various species of OPN15 have identified the conserved protein domains within the mature molecule. These domains include a number of N- and O-linked glycosylation sites, a poly-aspartic acid sequence of 7–10 consecutive aspartic residues, an RGD integrin recognition site, and a number of casein kinase II phosphorylation sites.16, 17 The OPN gene is ubiquitously expressed in all skeletal tissues during embryogenesis. However, it is not exclusively restricted to skeletal tissues since it is expressed at moderately high levels within developing kidneys.18 During the in vitro growth of primary osteoblast cultures, OPN expression shows a very early transient peak of expression, after these cells initially attach to their substrate, followed by a continued rise in expression that precedes that of osteocalcin and the mineralization of the ECM.19-22 Maximal levels of OPN expression are observed when osteoblasts reach full differentiation, and regulatory elements appear to control the promoter activity in both a skeletal tissue-specific manner and in response to AP-1–related activation.15 During skeletal tissue development in vivo, OPN expression reaches maximal levels of expression during postembryological bone development.23, 24 There is now considerable evidence that osteoclasts also express25 and synthesize OPN during bone remodeling,26 suggesting that this protein plays a more important role in postnatal skeletal tissue homeostasis than in initial skeletal tissue development. Extensive ultrastructural studies of OPN distribution in skeletal tissue ECMs illustrate that the protein is distributed throughout the mineralized areas of the bone and hypertrophic cartilage ECM. It is primarily associated with electron-dense areas of matrix-containing aggregates of other noncollagenous proteins that appear between collagen fibrils in the interfibrillar spaces of the ECM.27-29 One of the most unique aspects of OPN structural organization is its very specific association with boundary surfaces of skeletal tissues. These include the cement lines that demarcate matrix–matrix interfaces, such as that surrounding osteocytes and their canalicular processes and between lining cells and the underlying bone matrix.30 Other ultrastructural studies indicate that OPN localizes adjacent to the clear zones of resorptive osteoclasts.31 It has been proposed from these structural and immunocytochemical studies that OPN may have a functional role in providing tissue cohesion within the mineralized portions of the ECM where it is ubiquitously distributed and, likewise, might promote tissue and cellular adhesion at boundary surfaces such as at cement lines, the lamatan limitantes, and sites of matrix resorption.32 Numerous functional studies have focused on defining the role of OPN in bone metabolism. It was theorized that, due to its highly anionic and phosphorylated nature and its ability to tightly bind Ca2+ and hydroxyapatite,33, 34 phosphorylated proteins in general, and osteopontin in particular, played a role in the initiation and/or regulation of the mineralization process.33-37 A number of in vitro studies, however, indicate that OPN acts primarily as an inhibitor of mineral nucleation and growth,38, 39 raising the doubt that this molecule plays an important role in the initial deposition of the mineral in the matrix. The identification of the RGD sequence in the OPN molecule and its unique ultrastructural localization at resorption and boundary surfaces30 within the ECM of mineralized tissues led to other studies focusing on the function of the protein in mediating cell–matrix interactions through its RGD binding with specific integrin receptors.31, 40 Initial in vitro studies demonstrated that OPN promoted cellular adherence of a wide variety of cells including osteoblasts,13, 14 fibroblasts,41-43 macrophages, T-cells,44 and osteoclasts.45 The initial data, indicating that OPN specifically interacted with the αvβ3 integrin isotype40 and identification of αvβ3 integrin as one of the predominant cell adhesion receptors on the surface of osteoclasts.45-47 subsequently led to studies that have documented that osteopontin interaction with this receptor potentiates resorption,48, 49 while antagonism of this receptor interaction with OPN specifically inhibits bone resorption.50, 51 Finally, other data also suggest that both OPN, as well as other RGD-containing extracellular matrix proteins such as fibronectin and bone sialoprotein, may play important roles in directing cellular migration during skeletal growth or in defining the spatial boundaries of mineral deposition within the extracellular matrix.13, 52 Thus, the preponderance of functional and structural data to date suggest that the function of OPN in skeletal tissue is more associated with tissue remodeling and providing cells with positional information within the ECM and less of an inductive role in the mineralization process. Independent research efforts in both cancer biology and immunology identified that OPN plays an important role in aspects of metastasis and immunological response. OPN is an early, immediate-response gene during both T-cell53, 54 and macrophage activation.44 In addition, it is an AP-1–inducible gene following phorbol ester tumor promoter treatment in both epithelial55 and skeletal cells.56 Finally, it is identified independently as both a serum marker of malignant cell growth57 and as a component of metastatic tumors from a wide variety of primary tissue origins in mice and humans.58, 59 Numerous studies have shown OPN expression at varying levels in many tissues in conjunction with inflammatory processes induced either in response to infection or tissue injury.59 Considerable data have been accumulated which show that OPN is associated with a wide variety of pathologies including solid tumors, atherosclerotic plaques,60 granuloma tissue formation,61 as well as exogenous pathogen infection.62 The identification of an OPN interaction with the CD44 receptor also suggests that this molecule may use an alternate cell surface receptor to discriminate varying functions in these differing immunological processes in which it is involved.63 Common functions that have been ascribed to OPN in these differing pathologies have been its chemotaxis activities and its role in promoting adhesion of monocytes, macrophages, T-cells, and B-cells.59, 62 It is interesting to note the many common aspects of the remodeling cycle of bone in comparison with the biological events associated with inflammation and tissue repair in which OPN may be involved. Previous studies from several research groups have now shown that opn expression is responsive to mechanical stimulation within osteoblasts both in vitro64-67 and in vivo.5, 68 The current study by Terai et al.5 provides yet another study demonstrating that OPN expression is induced by physiologically relevant mechanical strains in vivo. OPN induction by mechanical stimulation also occurs in vascular smooth muscle cells69 and in the egg laying organ of chickens (M. Pines, personal communication). The induction of this gene therefore appears to be a common response to mechanical stimulation in many tissues, and its induction may serve a common function in tissue ECM remodeling that is needed in conjunction with the structural demands of the mechanical environment. The intracellular mechanisms that transduce mechanical stimuli are still poorly understood. However, a number of different signal transduction mechanisms including Ca2+ transients,70 cAMP/PKA stimulation,71 alterations in the cytoskeleton,67, 72, 73 and integrin mediated74, 75 second signal cascades are all activated by mechanical stimulation of osteoblasts. Examination of the mechanisms of mechano-signal transduction that induced opn expression demonstrated that the signal transduction process was a primary response through the activation of pre-existing transcription factors, dependent on the activation of a tyrosine kinase(s) and protein kinase A (PKA) or a PKA-like kinase, and dependent on microfilament integrity. These studies also demonstrated that mechanical stimuli activated focal adhesion kinase pp125FAK,67 which specifically transduces signals from integrin receptors. Subsequent studies demonstrated that the cell adhesion to fibronectin but not tissue culture plastic alone mimics the mechano-transduction of opn mRNA expression. Furthermore, integrin receptor(s) are involved in mediating the signal transduction processes of both cell attachment and mechanical stimulation, since incubation of osteoblasts with the integrin antagonists such as RGDS partially blocked the induction of opn expression in response to both stimuli.75 The induction of the opn expression, which itself is an integrin ligand, through both integrin occupancy and/or activation by mechanical stimulation, leads to the possibility that the molecules containing integrin binding domains such as RGDS may themselves behave like cytokines. The studies showing that osteoclast recruitment is blocked by the apparent antagonism of OPN function in mechanically stimulated resorption during orthodontic tooth movement5 provides further evidence supporting the idea that this molecule behaves in many ways like a cytokine. It is interesting to note that fibronectin and bone sialoprotein are also uniquely and separately regulated by mechanical stimulation, while osteocalcin and collagen are not (Carvalho, Schaffer, and Gerstenfeld, unpublished data). Such data provide further evidence that other integrin ligands may have an autocrine or paracrine function in regulating cellular function in the ECM. Indeed, these data show that the composition of the ECM, as regulated by mechanical stimuli, may itself have a specific feedback effect on the osteoblast, thereby providing a self-regulating mechanism of controlling ECM composition. Although the structural roles of the ECM are easily appreciated, their role in regulatory functions is only now becoming fully realized with the identification of the complexity of cellular receptors that interact with the ECM.76-79 The cellular logic of using these molecules to carry out regulatory function is both implicit and explicit. The implicit informational content of these molecules resides in the context of their spatial and temporal assembly in the matrix. These molecules therefore provide "positional information." As an example, OPN is synthesized both during early assembly and remodeling steps and later during the period when osteoblasts are synthesizing and mineralizing their ECM after the resorption process has reversed. Thus, during the initial periods of remodeling, transient OPN production provides important regulatory information for the recruitment and migration of osteoclasts into an active area of resorption. The incorporated OPN in the matrix, which had been previously laid down at the end of the last remodeling cycle, subsequently provides the latent structural mechanisms by which osteoclast attachment to mineralized matrix and its activation may be facilitated during a new round of remodeling. Other positional information imparted by OPN includes its role in regulating osteoclast polarity. Explicit information contained in ECM molecules is related to their receptor specificity. The specific ECM protein interactions with unique subsets of cellular receptors provides the means by which specific second signal kinase(s) cascades are activated and cellular responses initiated. As an example, recent data indicate that cellular adhesion to αvβ3 ligands activates a specific member of the focal adhesion kinase family, PYK2, and this kinase specifically interacts with src.80 Downstream from the activation of specific signal transduction cascades are wide-ranging numbers of cellular response, including specific gene activation, stimulation of cellular replication, or induction of apoptosis.77 While this review has focused only on the function of one ECM protein, OPN, a brief description is provided of other data that demonstrate the central role of the ECM in providing regulatory signals to cells. It has been recognized for some time that collagenous matrix itself provides crucial signals during the temporal differentiation of osteoblasts and experimentally this may be observed since osteoblasts growing in the absence of ascorbate (an essential cofactor in the synthesis of collagen) fail both to develop a collagenous matrix and to progress in their differentiation.20, 81, 82 Recently, a number of studies have shown that integrin ligation of α2 receptors is necessary for the ascorbate acid mediated induction of the osteogenic phenotype in cultures MC3T3 E-1.83-85 More specifically, these studies have identified both focal adhesion kinase (FAK) and mitogen-activated protein kinases as mediating the ascorbic acid induction. In one study, the specific activation of pre-existent CBFA transcriptional factor has been shown to be the mechanism of action by which the matrix induces osteogenic progression.85 In conclusion, the data presented in this perspective present the convergence of several different lines of research that provide an emerging picture that the ECM contributes its own set regulatory signals crucial for mediation, cellular formation, remodeling, and repair. We acknowledge Drs. Marc McKee, Jeff Berman, Joel Barnes, and Paul Kostenuick for their discussions and useful insights during the course of writing this review. We thank Drs. Mark Pines and Renny Franceschi for sharing their results before publication. Preparation of this review and studies in this laboratory on the mechano-induction of osteopontin are supported by a grant from the Department of Defense Bone Health and Military Medical Readiness Program.

Emergent technologies in regenerative medicine may soon overcome the limitations of conventional diabetes therapies. Collaborative efforts across the subfields of stem cell technology, islet encapsulation, and biomaterial carriers seek to produce a bioengineered pancreas capable of restoring endocrine function in patients with insulin-dependent diabetes. These technologies rely on a robust understanding of the extracellular matrix (ECM), the supportive 3-dimensional network of proteins necessary for cellular attachment, proliferation, and differentiation. Although these functions can be partially approximated by biosynthetic carriers, novel decellularization protocols have allowed researchers to discover the advantages afforded by the native pancreatic ECM. The native ECM has proven to be an optimal platform for recellularization and whole-organ pancreas bioengineering, an exciting new field with the potential to resolve the dire shortage of transplantable organs. This review seeks to contextualize recent findings, discuss current research goals, and identify future challenges of regenerative medicine as it applies to diabetes management.

With the remarkable increase in the fields of biomedical engineering and regenerative medicine, biomaterial design has become an indispensable approach for developing the biocompatible carriers for drug or gene cargo and extracellular matrix (ECM) for cell survival, proliferation and differentiation. Native ECM materials derived from animal tissues were believed to be the best choices for tissue engineering. However, possible pathogen contamination by cellular remnants from foreign animal tissues is an unavoidable issue that has limited the use of native ECM for human benefit. Some synthetic polymers have been used as alternative materials for manufacturing native ECM because of the biodegradability and ease of large-scale production of the polymers. However, the inherent polydispersity of the polymers causes batch-to-batch variation in polymer composition and possible cytotoxic interactions between chemical matrices and neighboring cells or tissues have not yet been fully resolved. Elastin-like proteins (ELPs) are genetically engineered biopolymers modeled after the naturally occurring tropoelastin and have emerged as promising materials for biomedical applications because they are biocompatible, non-immunogenic and biodegradable, and their composition, mechanical stiffness and even fate within the cell can be controlled at the gene level. This commentary highlights the recent progresses in the development of the ELP-based recombinant proteins that are being increasingly used for the delivery of chemotherapeutics and to provide a cell-friendly ECM environment.

Natural extracellular matrices (ECMs) perform the tasks necessary for tissue formation, maintenance, regulation and function, providing a powerful means of controlling the biological performance of regenerative materials. In addition, biomedical materials have claimed attention because of the increased interest in tissue engineering materials for wound care and regenerative medicine. Moreover, the nanostructure and morphological similarities with collagen make BC attractive for cell immobilization, cell support and Natural Extracellular Matrix (ECM) Scaffolds. In this work, we present the extracellular matrix (ECM) using the bacterial cellulose (Nanoskin®) which regulates cell behavior by influencing cell proliferation, survival, shape, migration and differentiation. Bacterial cellulose fermentation process is modified before the bacteria are inoculated for mimicking ECM to cells support and built new local material for wound healing. Chemical groups influences and thermal behavior in bacterial cellulose were analyzed using transmission infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA), respectively. Besides, In vivo analysis was evaluated with clinical study at Sharjah Kuwait Hospital.

Animal development starts as a single cell which proliferates into several new cells; these differentiate into highly specialized tissues, organs, and limbs; and the small but functioning organism eventually grows into its full scale. Throughout development the extracellular matrices, which are complex macromolecular networks, also undergo dramatic changes. Matrix transformations occasionally control the much more well‐studied changes in number and type of differentiating cells. Extracellular matrix (ECM) networks are typically broken down enzymatically to oligopeptides and are then resynthesized (remodeled) to form insoluble and nondiffusible macromolecular structures which confer stability of shape to multicellular systems. Mature ECM, such as skin, tendon, cartilage, and blood vessels, provides stiffness and strength to tissues and organs. Remodeling of ECM also occurs in adult organisms, during wound healing. An understanding of the role that ECM plays during development or wound healing can be obtained by use of synthetic ECM analogues. Several simple chemical ECM analogues have been synthesized and a few have been found to possess remarkable biological activity. One of these analogues has induced the partial regeneration of skin in an adult guinea pig wound model as well as in man. Peripheral nerve has been regenerated in another animal model by use of a similar ECM analogue. In all these mammalian lesions it is well‐known that regeneration does not occur spontaneously. These analogues are graft copolymers of collagen and chondroitin 6‐sulfate (a glycosaminoglycan) in the state of highly hydrated and covalently cross‐linked gels. Procedures are summarized for synthesis of copolymers with adjusted physicochemical properties, such as the rate at which they degrade enzymatically when implanted, the elements of their pore structure, and the degree of collagen crystallinity. ECM analogues have provided a novel window into the complexities of morphogenesis and regeneration and they have pointed towards entirely new directions in the medical treatment of serious organ dysfunction and organ loss. An ECM analogue has already become the basis of a new clinical treatment for massively burned patients. An interpretation of the results leads to a hypothesis about the nature of ECM during development. Since biological activity appears only when the physicochemical parameters fall within very narrow limits, it is intriguing to speculate that these experiments describe a single insoluble growth factor which is specific for skin synthesis. Such an insoluble growth factor appears to be just as essential to skin development as are the much more well‐known soluble growth factors. A different ECM analogue appears to induce nerve regeneration, possibly because each tissue requires its own developmentally active ECM.

The regulation of growth and metabolism of kidney stem cells with regional specificity using extracellular matrix derived from kidney

Hypochlorous acid-modified extracellular matrix contributes to the behavioral switching of human coronary artery smooth muscle cells

Biologics in Fistula Surgery: Parallels with Chronic Wounds

Biologic substrates, prepared by decellularizing and solubilizing tissues, have been of great interest in the tissue engineering field because of the preservation of complex biochemical constituents found in the native extracellular matrix (ECM). The integrity of the ECM is critical for cell behavior, adhesion, migration, differentiation, and proliferation that in turn affect homeostasis and tissue regeneration. Previous studies have shown that various processing methods have a distinctive way of affecting the composition of the decellularized ECM. In this study, we developed a bioactive substrate for hepatocytes in vitro, made of decellularized and solubilized liver tissue. The present work is a comparative approach of 2 different methods. First, we decellularized porcine liver tissue with ammonium hydroxide versus a sodium deoxycholate method, then characterized the decellularized tissue using various methods including double stranded DNA (dsDNA) content, DNA size, immunogenicity, and mass spectrometry. Second, we solubilized the decellularized porcine liver with hydrochloric acid versus acetic acid (AA) and characterized the resultant solubilized tissues using relevant methodologies including protein yield, immunogenicity, and bioactivity. Finally, we isolated primary porcine hepatocytes, cultured, and evaluated their bioactivity on the optimized decellularized–solubilized liver substrate. The decellularized porcine liver ECM processed by the ammonium hydroxide method and solubilized with AA displayed higher ECM integrity, low dsDNA, no evidence of intact nuclei, low human monocyte chemoattraction, and the presence of key molecules typically found in the native liver, a very important element for normal cell function. In addition, primary porcine hepatocytes showed enhanced functionality including albumin and urea production and bile canaliculi formation when cultured on the developed liver substrate compared to type I collagen.

Native extracellular matrix (ECM) provides structural support to the multicellular organism on a macroscopic scale and establishes a unique microenvironment (niche) to tissue- and organ-specific cell types. Both these functions are critical for optimal function of the organism. These natural ECMs comprise predominantly fibrillar proteins, collagen and elastin and are synthesized as monomers but undergo hierarchical organization into well-defined nanoscaled structural units. The interaction between the cells and ECM is dynamic, reciprocal and essential for tissue development, maintenance of function, repair and regeneration processes. Tissue-engineering scaffolds are synthetic, biomimetic ECM analogues that have great promise in regenerative medicine. Ongoing efforts in mimicking the native ECM in terms of composition and dimension have resulted in three strategies that permit the generation of scaffolds in nanometer dimensions. Although excellent reviews regarding the applications of these strategies in tissue engineering are available, a comprehensive review of the science behind these fabrication techniques does not exist. This review intends to fill this critical gap in the existing knowledge in the fast-expanding field of nanofibrous scaffolds. A thorough understanding of the fabrication processes would enable us to better exploit available technologies to produce superior tissue-engineering scaffolds.

Musculoskeletal injuries, including tendinopathies, present a significant clinical burden for aging populations. While the biological drivers of age‐related declines in tendon function are poorly understood, it is well accepted that dysregulation of extracellular matrix (ECM) remodeling plays a role in chronic tendon degeneration. Senescent cells, which have been associated with multiple degenerative pathologies in musculoskeletal tissues, secrete a highly pro‐inflammatory senescence‐associated secretory phenotype (SASP) that has potential to promote ECM breakdown. However, the role of senescent cells in the dysregulation of tendon ECM homeostasis is largely unknown. To assess this directly, we developed an in vitro model of induced cellular senescence in murine tendon explants. This novel technique enables us to study the isolated interactions of senescent cells and their native ECM without interference from age‐related systemic changes. We document multiple biomarkers of cellular senescence in induced tendon explants including cell cycle arrest, apoptosis resistance, and sustained inflammatory responses. We then utilize this in vitro senescence model to compare the ECM remodeling response of young, naturally aged, and induced‐senescent tendons to an altered mechanical stimulus. We found that both senescence and aging independently led to alterations in ECM‐related gene expression, reductions in protein synthesis, and tissue compositional changes. Furthermore, MMP activity was sustained, thus shifting the remodeling balance of aged and induced‐senescent tissues towards degradation over production. Together, this demonstrates that cellular senescence plays a role in the altered mechano‐response of aged tendons and likely contributes to poor clinical outcomes in aging populations.

As the cornerstone of tissue engineering and regeneration medicine research, developing a cost-effective and bionic extracellular matrix (ECM) that can precisely modulate cellular behavior and form functional tissue remains challenging. An artificial ECM combining polysaccharides and fibrillar proteins to mimic the structure and composition of natural ECM provides a promising solution for cardiac tissue regeneration. In this study, we developed a bionic hydrogel scaffold by combining a quaternized β-chitin derivative (QC) and fibrin-matrigel (FM) in different ratios to mimic a natural ECM. We evaluated the stiffness of those composite hydrogels with different mixing ratios and their effects on the growth of human umbilical vein endothelial cells (HUVECs). The optimal hydrogels, QCFM1 hydrogels were further applied to load HUVECs into nude mice for in vivo angiogenesis. Besides, we encapsulated human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) into QCFM hydrogels and employed 3D bioprinting to achieve batch fabrication of human-engineered heart tissue (hEHT). Finally, the myocardial structure and electrophysiological function of hEHT were evaluated by immunofluorescence and optical mapping. Designed artificial ECM has a tunable modulus (220-1380 Pa), which determines the different cellular behavior of HUVECs when encapsulated in these. QCFM1 composite hydrogels with optimal stiffness (800 Pa) and porous architecture were finally identified, which could adapt for in vitro cell spreading and in vivo angiogenesis of HUVECs. Moreover, QCFM1 hydrogels were applied in 3D bioprinting successfully to achieve batch fabrication of both ring-shaped and patch-shaped hEHT. These QCFM1 hydrogels-based hEHTs possess organized sarcomeres and advanced function characteristics comparable to reported hEHTs. The chitin-derived hydrogels are first used for cardiac tissue engineering and achieve the batch fabrication of functionalized artificial myocardium. Specifically, these novel QCFM1 hydrogels provided a reliable and economical choice serving as ideal ECM for application in tissue engineering and regeneration medicine.

Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture