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Chemistry of collagen / by Joseph R. Kanagy.

Chemistry of collagen / edited by G. N. Ramachandran.

The chemistry and reactivity of collagen / by K.H. Gustavson.

The macromolecular chemistry of gelatin / by Athur Veis.

Conservation of leather : and related materials / Marion Kite and Roy Thomson.

Cell structure and its interpretation : essays presented to John Randal Baker F.R.S / ed. by S.M.McGee-Russell and K.F.A.Ross.

Biotechnology : in context.

Gale Encyclopedia of Science.

Collagen, the most abundant extracellular matrix protein in animal kingdom belongs to a family of fibrous proteins, which transfer load in tissues and which provide a highly biocompatible environment for cells. This high biocompatibility makes collagen a perfect biomaterial for implantable medical products and scaffolds for in vitro testing systems. To manufacture collagen based solutions, porous sponges, membranes and threads for surgical and dental purposes or cell culture matrices, collagen rich tissues as skin and tendon of mammals are intensively processed by physical and chemical means. Other tissues such as pericardium and intestine are more gently decellularized while maintaining their complex collagenous architectures. Tissue processing technologies are organized as a series of steps, which are combined in different ways to manufacture structurally versatile materials with varying properties in strength, stability against temperature and enzymatic degradation and cellular response. Complex structures are achieved by combined technologies. Different drying techniques are performed with sterilisation steps and the preparation of porous structures simultaneously. Chemical crosslinking is combined with casting steps as spinning, moulding or additive manufacturing techniques. Important progress is expected by using collagen based bio-inks, which can be formed into 3D structures and combined with live cells. This review will give an overview of the technological principles of processing collagen rich tissues down to collagen hydrolysates and the methods to rebuild differently shaped products. The effects of the processing steps on the final materials properties are discussed especially with regard to the thermal and the physical properties and the susceptibility to enzymatic degradation. These properties are key features for biological and clinical application, handling and metabolization.

Biomedical engineering online, 2019-03, Vol.18 (1), p.24-74, Article 24

Processing of collagen based biomaterials and the resulting materials properties

The extracellular matrix (ECM) is a complex assembly of structural proteins that provides physical support and biochemical signaling to cells in tissues. The mechanical properties of the ECM have been found to play a key role in regulating cell behaviors such as differentiation and malignancy. Gels formed from ECM protein biopolymers such as collagen or fibrin are commonly used for 3D cell culture models of tissue. One of the most striking features of these gels is that they exhibit nonlinear elasticity, undergoing strain stiffening. However, these gels are also viscoelastic and exhibit stress relaxation, with the resistance of the gel to a deformation relaxing over time. Recent studies have suggested that cells sense and respond to both nonlinear elasticity and viscoelasticity of ECM, yet little is known about the connection between nonlinear elasticity and viscoelasticity. Here, we report that, as strain is increased, not only do biopolymer gels stiffen but they also exhibit faster stress relaxation, reducing the timescale over which elastic energy is dissipated. This effect is not universal to all biological gels and is mediated through weak cross-links. Mechanistically, computational modeling and atomic force microscopy (AFM) indicate that strain-enhanced stress relaxation of collagen gels arises from force-dependent unbinding of weak bonds between collagen fibers. The broader effect of strain-enhanced stress relaxation is to rapidly diminish strain stiffening over time. These results reveal the interplay between nonlinear elasticity and viscoelasticity in collagen gels, and highlight the complexity of the ECM mechanics that are likely sensed through cellular mechanotransduction.

Proceedings of the National Academy of Sciences - PNAS, 2016-05, Vol.113 (20), p.5492-5497

Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels

Hydrolyzed collagen (HC) is a group of peptides with low molecular weight (3-6 KDa) that can be obtained by enzymatic action in acid or alkaline media at a specific incubation temperature. HC can be extracted from different sources such as bovine or porcine. These sources have presented health limitations in the last years. Recently research has shown good properties of the HC found in skin, scale, and bones from marine sources. Type and source of extraction are the main factors that affect HC properties, such as molecular weight of the peptide chain, solubility, and functional activity. HC is widely used in several industries including food, pharmaceutical, cosmetic, biomedical, and leather industries. The present review presents the different types of HC, sources of extraction, and their applications as a biomaterial.

Molecules (Basel, Switzerland), 2019-11, Vol.24 (22), p.4031

Hydrolyzed Collagen-Sources and Applications

There is growing appreciation of the role that the extracellular environment plays in regulating cell behavior. Mechanical, structural, and compositional cues, either alone or in concert, can drastically alter cell function. Biomaterials, and particularly hydrogels, have been developed and implemented to present defined subsets of these cues for investigating countless cellular processes as a means of understanding morphogenesis, aging, and disease. Although most scientists concede that standard cell culture materials (tissue culture plastic and glass) do a poor job of recapitulating native cellular milieus, there is currently a knowledge barrier for many researchers in regard to the application of hydrogels for cell culture. Here, we introduce hydrogels to those who may be unfamiliar with procedures to culture and study cells with these systems, with a particular focus on commercially available hydrogels.

Nature methods, 2016-05, Vol.13 (5), p.405-414

A practical guide to hydrogels for cell culture

In this work, we constructed a Collagen I–Matrigel composite extracellular matrix (ECM). The composite ECM was used to determine the influence of the local collagen fiber orientation on the collective intravasation ability of tumor cells. We found that the local fiber alignment enhanced cell–ECM interactions. Specifically, metastatic MDA-MB-231 breast cancer cells followed the local fiber alignment direction during the intravasation into rigid Matrigel (∼10 mg/mL protein concentration).

Proceedings of the National Academy of Sciences - PNAS, 2016-10, Vol.113 (40), p.11208-11213

Oriented collagen fibers direct tumor cell intravasation

Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents.
Bone is a natural composite of collagen and hydroxyapatite but, surprising, little is known about its characteristics at the molecular scale. Nair
et al
. conduct molecular-scale simulations of mineralized collagen networks to better understand how bone achieves superior mechanical properties to its constituents.

Nature communications, 2013-04, Vol.4 (1), p.1724-1724, Article 1724

Molecular mechanics of mineralized collagen fibrils in bone

Spider silk is extraordinarily strong, mollusk shells and bone are tough, and porcupine quills and feathers resist buckling. How are these notable properties achieved? The building blocks of the materials listed above are primarily minerals and biopolymers, mostly in combination; the first weak in tension and the second weak in compression. The intricate and ingenious hierarchical structures are responsible for the outstanding performance of each material. Toughness is conferred by the presence of controlled interfacial features (friction, hydrogen bonds, chain straightening and stretching); buckling resistance can be achieved by filling a slender column with a lightweight foam. Here, we present and interpret selected examples of these and other biological materials. Structural bio-inspired materials design makes use of the biological structures by inserting synthetic materials and processes that augment the structures' capability while retaining their essential features. In this Review, we explain this idea through some unusual concepts.

Science (American Association for the Advancement of Science), 2013-02, Vol.339 (6121), p.773-779

Structural Biological Materials: Critical Mechanics-Materials Connections

Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of
Cthrc1
(collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and
CTHRC1
-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of
Cthrc1
-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.
Collagen production by lung cells is critical to maintain organ architecture but can also drive pathological scarring. Here the authors perform single cell RNA sequencing of collagen-producing lung cells identifying a subset of pathologic fibroblasts characterized by Cthrc1 expression which are concentrated within fibroblastic foci in fibrotic lungs and show a pro-fibrotic phenotype.

Nature communications, 2020-04, Vol.11 (1), p.1920-1920, Article 1920

Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis

Hydrogels from different materials can be used in biomedical field as an innovative approach in regenerative medicine. Depending on the origin source, hydrogels can be synthetized through chemical and physical methods. Hydrogel can be characterized through several physical parameters, such as size, elastic modulus, swelling and degradation rate. Lately, research is focused on hydrogels derived from biologic materials. These hydrogels can be derived from protein polymers, such as collage, elastin, and polysaccharide polymers like glycosaminoglycans or alginate among others. Introduction of decellularized tissues into hydrogels synthesis displays several advantages compared to natural or synthetic based hydrogels. Preservation of natural molecules such as growth factors, glycans, bioactive cryptic peptides and natural proteins can promote cell growth, function, differentiation, angiogenesis, anti-angiogenesis, antimicrobial effects, and chemotactic effects. Versatility of hydrogels make possible multiple applications and combinations with several molecules on order to obtain the adequate characteristic for each scope. In this context, a lot of molecules such as cross link agents, drugs, grow factors or cells can be used. This review focuses on the recent progress of hydrogels synthesis and applications in order to classify the most recent and relevant matters in biomedical field.

Journal of materials science. Materials in medicine, 2019-10, Vol.30 (10), p.115-10, Article 115

Overview of natural hydrogels for regenerative medicine applications

Collagens are the most abundant high molecular weight proteins in both invertebrate and vertebrate organisms, including mammals, and possess mainly a structural role, existing different types according with their specific organization in distinct tissues. From this, they have been elected as one of the key biological materials in tissue regeneration approaches. Also, industry is constantly searching for new natural sources of collagen and upgraded methodologies for their production. The most common sources are from bovine and porcine origin, but other ways are making their route, such as recombinant production, but also extraction from marine organisms like fish. Different organisms have been proposed and explored for collagen extraction, allowing the sustainable production of different types of collagens, with properties depending on the kind of organism (and their natural environment) and extraction methodology. Such variety of collagen properties has been further investigated in different ways to render a wide range of applications. The present review aims to shed some light on the contribution of marine collagens for the scientific and technological development of this sector, stressing the opportunities and challenges that they are and most probably will be facing to assume a role as an alternative source for industrial exploitation.

Marine drugs, 2014-12, Vol.12 (12), p.5881-5901

Marine origin collagens and its potential applications

The integration of muscle cells with soft robotics in recent years has led to the development of biohybrid machines capable of untethered locomotion. A major frontier that currently remains unexplored is neuronal actuation and control of such muscle-powered biohybrid machines. As a step toward this goal, we present here a biohybrid swimmer driven by on-board neuromuscular units. The body of the swimmer consists of a free-standing soft scaffold, skeletal muscle tissue, and optogenetic stem cell-derived neural cluster containing motor neurons. Myoblasts embedded in extracellular matrix self-organize into a muscle tissue guided by the geometry of the scaffold, and the resulting muscle tissue is cocultured in situ with a neural cluster. Motor neurons then extend neurites selectively toward the muscle and innervate it, developing functional neuromuscular units. Based on this initial construct, we computationally designed, optimized, and implemented light-sensitive flagellar swimmers actuated by these neuromuscular units. Cyclic muscle contractions, induced by neural stimulation, drive time-irreversible flagellar dynamics, thereby providing thrust for untethered forward locomotion of the swimmer. Overall, this work demonstrates an example of a biohybrid robot implementing neuromuscular actuation and illustrates a path toward the forward design and control of neuron-enabled biohybrid machines.

Proceedings of the National Academy of Sciences - PNAS, 2019-10, Vol.116 (40), p.19841-19847

Neuromuscular actuation of biohybrid motile bots

Osteoarthritis affects millions of people worldwide but current treatments using analgesics or anti-inflammatory drugs only alleviate symptoms of this disease. Here, we present an injectable, biodegradable piezoelectric hydrogel, made of short electrospun poly-L-lactic acid nanofibers embedded inside a collagen matrix, which can be injected into the joints and self-produce localized electrical cues under ultrasound activation to drive cartilage healing. In vitro, data shows that the piezoelectric hydrogel with ultrasound can enhance cell migration and induce stem cells to secrete TGF-β1, which promotes chondrogenesis. In vivo, the rabbits with osteochondral critical-size defects receiving the ultrasound-activated piezoelectric hydrogel show increased subchondral bone formation, improved hyaline-cartilage structure, and good mechanical properties, close to healthy native cartilage. This piezoelectric hydrogel is not only useful for cartilage healing but also potentially applicable to other tissue regeneration, offering a significant impact on the field of regenerative tissue engineering.
The use of biomaterial scaffolds-based cartilage grafts could potentially innovate the Osteoarthritis (OA) treatment, but has been limited by toxicity concerns and invasive surgical procedures. Here, the authors report an injectable and biodegradable piezoelectric hydrogel with ultrasound activation to offer a minimally invasive approach for OA treatment.