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The effect of source animal age upon the in vivo remodeling characteristics of an extracellular matrix scaffold.

ABSTRACT: Biologic scaffolds composed of mammalian extracellular matrix (ECM) are routinely used for the repair and reconstruction of injured or missing tissues in a variety of pre-clinical and clinical applications. However, the structural and functional outcomes have varied considerably. An important variable of xenogeneic biologic scaffolds is the age of the animal from which the ECM is derived. The present study compared the in vivo host response and remodeling outcomes of biologic scaffolds composed of small intestinal submucosa (SIS)-ECM harvested from pigs that differed only in age. Results showed that there are distinct differences in the remodeling characteristics as a consequence of source animal age. Scaffolds derived from younger animals were associated with a more constructive, site appropriate, tissue remodeling response than scaffolds derived from older animals. Furthermore, the constructive remodeling response was associated with a dominant M2 macrophage response.

SUBMITTER: Sicari BM

PROVIDER: S-EPMC3569720 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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The effect of source animal age upon the in vivo remodeling characteristics of an extracellular matrix scaffold.

Sicari Brian M BM Johnson Scott A SA Siu Bernard F BF Crapo Peter M PM Daly Kerry A KA Jiang Hongbin H Medberry Christopher J CJ Tottey Stephen S Turner Neill J NJ Badylak Stephen F SF

Biomaterials 20120509 22

Biologic scaffolds composed of mammalian extracellular matrix (ECM) are routinely used for the repair and reconstruction of injured or missing tissues in a variety of pre-clinical and clinical applications. However, the structural and functional outcomes have varied considerably. An important variable of xenogeneic biologic scaffolds is the age of the animal from which the ECM is derived. The present study compared the in vivo host response and remodeling outcomes of biologic scaffolds composed ...[more]

PMID: 22575834

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Project description:The immunological potential of animal-derived tissues and organs is the critical hurdle to increasing their clinical implementation. Glutaraldehyde-fixation cross-links proteins in xenogeneic tissues (e.g., bovine pericardium) to delay immune rejection, but also compromises the regenerative potential of the resultant biomaterial. Unfixed xenogeneic biomaterials in which xenoantigenicity has been ameliorated and native extracellular matrix (ECM) architecture has been maintained have the potential to overcome limitations of current clinically utilized glutaraldehyde-fixed biomaterials. The objective of this work was to determine how residual antigenicity and ECM architecture preservation modulate recipient immune and regenerative responses towards unfixed bovine pericardium (BP) ECM scaffolds. Disruption of ECM architecture during scaffold generation, with either SDS-decellularization or glutaraldehyde-fixation, stimulated recipient foreign body response and resultant fibrotic encapsulation following leporine subpannicular implantation. Conversely, BP scaffolds subjected to stepwise removal of hydrophilic and lipophilic antigens using amidosulfobetaine-14 (ASB-14) maintained native ECM architecture and thereby avoided fibrotic encapsulation. Removal of hydrophilic and lipophilic antigens significantly decreased local and systemic graft-specific, adaptive immune responses and subsequent calcification of BP scaffolds compared to scaffolds undergoing hydrophile removal only. Critically, removal of antigenic components and preservation of ECM architecture with ASB-14 promoted full-thickness recipient non-immune cellular repopulation of the BP scaffold. Further, unlike clinically utilized fixed BP, ASB-14-treated scaffolds fostered rapid intimal and medial vessel wall regeneration in a porcine carotid patch angioplasty model. This work highlights the importance of residual antigenicity and ECM architecture preservation in modulating recipient immune and regenerative responses towards xenogeneic biomaterial generation.

Project description:A naturally occurring mutation in the PRNP gene of Norwegian dairy goats terminates synthesis of the cellular prion protein (PrPC), rendering homozygous goats (PRNPTer/Ter) devoid of the protein. Although PrPC has been extensively studied, particularly in the central nervous system, the biological role of PrPC remains incompletely understood. Here, we examined whether loss of PrPC affects the initial stage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Acute pulmonary inflammation was induced by intravenous injection of LPS (Escherichia coli O26:B6) in 16 goats (8 PRNPTer/Ter and 8 PRNP+/+). A control group of 10 goats (5 PRNPTer/Ter and 5 PRNP+/+) received sterile saline. Systemic LPS challenge induced sepsis-like clinical signs including tachypnea and respiratory distress. Microscopic examination of lungs revealed multifocal areas with alveolar hemorrhages, edema, neutrophil infiltration, and higher numbers of alveolar macrophages, with no significant differences between PRNP genotypes. A total of 432 (PRNP+/+) and 596 (PRNPTer/Ter) genes were differentially expressed compared with the saline control of the matching genotype. When assigned to gene ontology categories, biological processes involved in remodeling of the extracellular matrix (ECM), were exclusively enriched in PrPC-deficient goats. These genes included a range of collagen-encoding genes, and proteases such as matrix metalloproteinases (MMP1, MMP2, MMP14, ADAM15) and cathepsins. Several proinflammatory upstream regulators (TNF-?, interleukin-1?, IFN-?) showed increased activation scores in goats devoid of PrPC. In conclusion, LPS challenge induced marked alterations in the lung tissue transcriptome that corresponded with histopathological and clinical findings in both genotypes. The increased activation of upstream inflammatory regulators and enrichment of ECM components could reflect increased inflammation in the absence of PrPC. Further studies are required to elucidate whether these alterations may affect the later reparative phase of ALI.

Dataset Information

The effect of source animal age upon the in vivo remodeling characteristics of an extracellular matrix scaffold.

Publications

The effect of source animal age upon the in vivo remodeling characteristics of an extracellular matrix scaffold.

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