Extracellular matrix as an inductive scaffold for functional tissue reconstruction

Abstract

The extracellular matrix (ECM) is a meshwork of both structural and functional proteins assembled in unique tissue-specific architectures. The ECM both provides the mechanical framework for each tissue and organ and is a substrate for cell signaling. The ECM is highly dynamic, and cells both receive signals from the ECM and contribute to its content and organization. This process of "dynamic reciprocity" is key to tissue development and for homeostasis. Based upon these important functions, ECM-based materials have been used in a wide variety of tissue engineering and regenerative medicine approaches to tissue reconstruction. It has been demonstrated that ECM-based materials, when appropriately prepared, can act as inductive templates for constructive remodeling. Specifically, such materials act as templates for the induction of de novo functional, site-appropriate, tissue formation. Herein, the diverse structural and functional roles of the ECM are reviewed to provide a rationale for the use of ECM scaffolds in regenerative medicine. Translational examples of ECM scaffolds in regenerative are provided, and the potential mechanisms by which ECM scaffolds elicit constructive remodeling are discussed. A better understanding of the ability of ECM scaffold materials to define the microenvironment of the injury site will lead to improved clinical outcomes associated with their use.

Fig 1

Use of extracellular matrix (ECM) scaffold material for reconstruction post endomucosal resection (EMR) in a canine model. Schematic of the surgical deployment of ECM device with an achalasia balloon and delivery of the surgical adhesive (A). EMR is performed and tubular ECM scaffold is deployed using achalasia balloon. A lysine-derive urethane surgical adhesive (TissuGlu, Cohera Medical) was used to secure ECM scaffold in place. Balloon was inflated and maintained for 15 minutes to allow adherence of the ECM scaffold to the esophagus prior to removal. Gross view of the remodeling EMR areas at 2 months after surgery (B, C). The control (B) shows pronounced stricture with reductions in the circumference and the length of the injury site. In contrast, the EMR site treated with ECM shows a smooth mucosal surface and limited circumferential and longitudinal reduction (C). Reproduced from with permission from Elsevier.

Fig 2

Use of extracellular matrix (ECM) as a template for reconstruction of the temporomandibular joint (TMJ) disk. An ECM scaffold (A) composed of porcine urinary bladder matrix was placed into the TMJ space (C, arrow indicates implant) following removal of the TMJ disk (B). Results demonstrated that the material was rapidly remodeled, acting as an interpositional material between the condyle and fossa (D). At explant the remodeled disk (E, arrow indicates explanted material) highly resembled native tissue (F). This tissue was also histologically and biomechanically similar to native tissues (not shown) and was shown to include integration with the lateral muscular and ligamentous attachments. This was in direct contrast to the contralateral side (G), which was left empty and resulted in the deposition of a small amount of granulation tissue and significant degenerative changes to the joint.

Fig 3

Overview of the constructive remodeling process associated with extracellular matrix (ECM) scaffold implantation. Scaffold materials obtained from tissue decellularization are processed into application specific formulations. Upon implantation, the material provides a microenvironment for ingrowth of cells and mechanotransduction. The material is degraded rapidly resulting in modulation of the innate and adaptive immune response and recruitment of progenitor cells. Over time, these processes result in constructive remodeling–the formation of new, site appropriate, functional host tissues. Reproduced from with permission from Elsevier.

Fig 4

Outcomes following 14- and 35-day implantation of 3 different extracellular matrix (ECM) based biomaterials in a rodent abdominal wall defect model. Results demonstrated that those scaffold materials, which were cross-linked (Collamend, Bard) were associated with a foreign body type response and an M1 type macrophage response (A–C). Scaffold materials, which were not cross-linked but degraded slowly (InteXen, American Medical Systems), were associated with a dense mononuclear cell response early, with reduction of the inflammatory response at later times (D–E). These materials were associated with a mixed M1/M2 macrophage phenotype (F). Scaffold materials, which were noncross-linked and degraded rapidly (MatriStem, ACell), were associated with a more polarized M2 response and showed signs of early constructive remodeling (G–I). Hematoxylin and eosin (A, B, D, E, G, H) and immunofluorescent labeling of macrophages (14 days) are shown. Image magnification = ×40. Scale bar = 100 μm. CD68 (pan-macrophage) = red, CCR7 (M1) = orange, CD206 (M2) = green, DRAQ5 (nuclei) = blue. Arrow = interface between scaffold and underlying native tissue. Asterisk = new skeletal muscle bundle formation. Reproduced from with permission from Elsevier.