Fibroblasts can condense a hydrated collagen lattice to a tissue-like structure 1/28th the area of the starting gel in 24 hr. The rate of the process can be regulated by varying the protein content of the lattice, the cell number, or the con- centration of an inhibitor such as Colcemid. Fibroblasts of high population doubling level propagated in vitro, which have left the cell cycle, can carry out the contraction at least as efficiently as cycling cells. The potential uses of the system as an immu- nologically tolerated "tissue" for wound hea ing and as a model for studying fibroblast function are discussed.

Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative

Novel drug delivery systems and disease models for pulmonary fibrosis.

Abstract Bioprinting has attracted much attention due to its suitability for fabricating biomedical devices. In particular, bioprinting has become one of the growing centers in the field of wound healing, with various types of bioprinted devices being developed, including 3D scaffolds, microneedle patches, and flexible electronics. Bioprinted devices can be designed with specific biostructures and biofunctions that closely match the shape of wound sites and accelerate the regeneration of skin through various approaches. Herein, a comprehensive review of the bioprinting of smart wound dressings is presented, emphasizing the crucial effect of bioprinting in determining biostructures and biofunctions. The review begins with an overview of bioprinting techniques and bioprinted devices, followed with an in‐depth discussion of polymer‐based inks, modification strategies, additive ingredients, properties, and applications. The strategies for the modification of bioprinted devices are divided into seven categories, including chemical synthesis of novel inks, physical blending, coaxial bioprinting, multimaterial bioprinting, physical absorption, chemical immobilization, and hybridization with living cells, and examples are presented. Thereafter, the frontiers of bioprinting and wound healing, including 4D bioprinting, artificial intelligence‐assisted bioprinting, and in situ bioprinting, are discussed from a perspective of interdisciplinary sciences. Finally, the current challenges and future prospects in this field are highlighted. 

Emerging Bioprinting for Wound Healing.

Fibrin is a promising natural polymer that is widely used for diverse applications, such as hemostatic glue, carrier for drug and cell delivery, and matrix for tissue engineering. Despite the significant advances in the use of fibrin for bioengineering and biomedical applications, some of its characteristics must be improved for suitability for general use. For example, fibrin hydrogels tend to shrink and degrade quickly after polymerization, particularly when they contain embedded cells. In addition, their poor mechanical properties and batch-to-batch variability affect their handling, long-term stability, standardization, and reliability. One of the most widely used approaches to improve their properties has been modification of the structure and composition of fibrin hydrogels. In this review, recent advances in composite fibrin scaffolds, chemically modified fibrin hydrogels, interpenetrated polymer network (IPN) hydrogels composed of fibrin and other synthetic or natural polymers are critically reviewed, focusing on their use for tissue engineering. 

Technological advances in fibrin for tissue engineering

A major pathogenic feature of fibrotic diseases is the excessive and disorganized deposition of collagens. This results from changes in both synthetic and degradative pathways. The posttranslational hydroxylation of proline to hydroxyproline and the relative abundance of hydroxyproline in collagens, compared with other proteins, facilitates its use as a relatively specific marker of collagen content and metabolism. This chapter describes in vivo methods for the estimation of collagen synthesis and degradation rates, as well as the proportion of newly synthesised collagen rapidly degraded intracellularly. These pathways have all been shown to play important roles in the altered deposition of collagen associated with the development of fibrosis. The methods are based on the incorporation of radiolabeled proline into collagen as hydroxyproline and its measurement in intact protein and collagen breakdown products. In addition, an accurate and highly sensitive high-performance liquid chromatography method is described for the measurement of hydroxyproline for in vivo and in vitro studies.

Methods for measuring hydroxyproline and estimating in vivo rates of collagen synthesis and degradation.

Biofabrication techniques have enabled the formation of complex models of many biological tissues. We present a framework to contextualize biofabrication techniques within a disease modeling application. Fibrosis is a progressive disease interfering with tissue structure and function, which stems from an aberrant wound healing response. Epithelial injury and clot formation lead to fibroblast invasion and activation, followed by contraction and remodeling of the extracellular matrix. These stages have healthy wound healing variants in addition to the pathogenic analogs that are seen in fibrosis. This review evaluates biofabrication of a variety of phenotypic cell-based fibrosis assays. By recapitulating different contributors to fibrosis, these assays are able to evaluate biochemical pathways and therapeutic candidates for specific stages of fibrosis pathogenesis. Biofabrication of these culture models may enable phenotypic screening for improved understanding of fibrosis biology as well as improved screening of anti-fibrotic therapeutics.

/pdf/biofabrication-of-phenotypic-pulmonary-fibrosis-assays-2pkb0a5fzc.pdf

Biofabrication of phenotypic pulmonary fibrosis assays.

This paper describes printing of microscale fibroblast-laden matrices using an aqueous two-phase approach that controls thrombin-mediated enzymatic crosslinking of fibrin. Optimization of aqueous two-phase formulations enabled polymerization of consistent sub-microliter volumes of cell-laden fibrin. When plasminogen was added to these micro-scaffolds, the primary normal human lung fibroblasts converted it to plasmin, triggering gradual degradation of the fibrin. Time-lapse live-cell imaging and automated image analysis provided readouts of time to degradation of 50% of the scaffold as well as maximum degradation rate. The time required for degradation decreased linearly with cell number while it increased in a dose-dependent manner upon addition of TGF-β1. Fibroblasts isolated from idiopathic pulmonary fibrosis patients showed similar trends with regards to response to TGF-β1 stimulation. Addition of reactive oxygen species (ROS) slowed fibrinolysis but only in the absence of TGF-β1, consistent with published studies demonstrating that pro-fibrotic cellular phenotypes induced by TGF-β1 are mediated, at least in part, through increased production of ROS. FDA-approved and experimental anti-fibrosis drugs were also tested for their effects on fibrinolysis rates. Given the central role of fibrinolysis in both normal and pathogenic wound healing of various tissues, the high-throughput cell-mediated fibrinolysis assay described has broad applicability in the study of many different cell types and diseases. Furthermore, aqueous two-phase printing of fibrin addresses several current limitations of fibrin bio-inks, potentially enabling future applications in tissue engineering andin vitromodels.

Aqueous two-phase deposition and fibrinolysis of fibroblast-laden fibrin micro-scaffolds.

This paper describes a microscale fibroplasia and contraction model that is based on fibrin-embedded lung fibroblasts and provides a convenient visual readout of fibrosis. Cell-laden fibrin microgel drops are formed by aqueous two-phase microprinting. The cells deposit extracellular matrix (ECM) molecules such as collagen while fibrin is gradually degraded. Ultimately, the cells contract the collagen-rich matrix to form a compact cell-ECM spheroid. The size of the spheroid provides the visual readout of the extent of fibroplasia. Stimulation of this wound-healing model with the profibrotic cytokine TGF-β1 leads to an excessive scar formation response that manifests as increased collagen production and larger cell-ECM spheroids. Addition of drugs also shifted the scarring profile: the FDA-approved fibrosis drugs (nintedanib and pirfenidone) and a PAI-1 inhibitor (TM5275) significantly reduced cell-ECM spheroid size. Not only is the assay useful for evaluation of antifibrotic drug effects, it is relatively sensitive; one of the few in vitro fibroplasia assays that can detect pirfenidone effects at submillimolar concentrations. Although this paper focuses on lung fibrosis, the approach opens opportunities for studying a broad range of fibrotic diseases and for evaluating antifibrotic therapeutics.

Contracting scars from fibrin drops.

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Papers

Biofabrication of phenotypic pulmonary fibrosis assays.

Aqueous two-phase deposition and fibrinolysis of fibroblast-laden fibrin micro-scaffolds.

Contracting scars from fibrin drops.