Complex Problem, Simple Solution: Using Endoform to Provide a Functional Extracellular Matrix in Chronic Wounds

Typical approaches to chronic wound care involve working to an algorithm and employing prompted steps to overcome barriers to healing such as necrosis, insufficient perfusion, and excessive protease activity. This standardized approach is efficient and easy to train to, but it is important to understand the mechanisms that underpin wound pathology and successful healing, many of which are related to the extracellular matrix (ECM).

In the simplest terms, skin comprises 2 components: cells (eg, endothelial, inflammatory, and fibroblast) and ECM. The ECM is a complex network of biomolecules that serves as a structural medium for cells and provides tissues with physical properties such as strength and elasticity. More than just a physical structure, the ECM plays a major role in influencing cell behavior via dynamic and reciprocal interactions between cells and the ECM.¹ In wounds, the ECM and associated cells are missing or damaged; in chronic wounds, the ECM is unable to support normal healing — rampant protease activity results in ECM destruction that exceeds the rate of ECM repair.² Although the ECM of skin is primarily comprised of collagens, the ECM is made up of hundreds of other components, and the composition of the ECM is constantly changing based on interactions among cells and the environment.

Advances in modern regenerative medicine have shown that supplementing the chronic wound environment with a functional ECM is a key strategy in overcoming stalled healing and progressing wounds to the proliferative phase of healing.² These ECM technologies are more than collagen dressings; instead, they are designed to mimic the patient’s ECM in terms of structure and composition. Endoform (Aroa Biosurgery Limited, Auckland, New Zealand) is an advanced ECM biomaterial indicated for use in wound healing and soft tissue reconstruction. Derived from the forestomach of  sheep, Endoform is minimally processed to selectively remove ovine cells while preserving the beneficial compositional and structural profile of native ECM. Proteomic studies have demonstrated Endoform to be made up of more than 150 unique matrix proteins, a degree of compositional complexity similar to that of native tissue ECM.^3,4 In addition to its biological diversity, Endoform retains the native fiber arrangement and porous structure of tissue ECM, enabling cell adhesion, migration, and proliferation.

The introduction of advanced ECM technologies such as Endoform has bought about a paradigm shift in modern wound management. No longer are we simply managing the symptoms of chronic wounds (eg, pain, malodor, and exudate); we also are actively addressing the underlying pathology — that is, a missing or damaged ECM. In the chronic wound environment, these advanced ECM technologies serve 2 roles: 1) ECM can address the underlying chronicity, and 2) ECM provides the structure for  cell repopulation of the wound defect to actively build tissue.

In the chronic wound environment, tissue ECM is readily degraded by elevated wound proteases, leading to the prolonged nonhealing state. As a mimic of tissue ECM, Endoform also is degraded by elevated protease activity in chronic wounds. This phenomenon is readily visible and provides a simple and effective way to observe the proteolytic state of the wound.^5,6 As Endoform is degraded by proteases, it forms a golden proteinaceous gel similar in appearance to slough (see Figure). The similarities in appearance to wound slough should not be surprising, given that wound slough and residual Endoform both comprise enzymatically digested ECM fragments. One important distinction is that it is not necessary to remove residual Endoform because it contains ECM components that aid healing and protease modulation.

Although the ECM found in tissue and Endoform both are digested by wound proteases, ECM components also play a critical role in regulating protease activity in the chronic wound environment. For example, Endoform exhibits a diverse array of different collagen types4 with preserved native matrix structure.⁷ This natural complexity allows Endoform to modulate a far wider range of matrix metalloproteinases compared with traditional collagen dressings comprised of only denatured collagen I.⁸ Similarly, the presence of elastin in Endoform attenuates the activity of neutrophil elastase, something not seen traditional reconstituted collagen dressings.⁸ In addition, recent analysis has revealed that similar to tissue ECM, Endoform contains tissue inhibitors of metalloproteinases,⁴ supporting the conclusion that Endoform’s protease modulation is mediated by multiple mechanisms in a fashion similar to that regulated by functional tissue ECM.

Once excessive wound protease activity is controlled, a functional ECM facilitates the rebuilding of damaged tissues. Secondary ECM molecules such as fibronectin and laminin facilitate cell adhesion and migration.³ Growth factors bound to the ECM are released via regulated cell-ECM interactions to recruit cells and signal differentiation to encourage angiogenesis and ultimately epithelialization.⁹ In retaining this diverse makeup of secondary molecules, Endoform mimics functional tissue ECM to encourage constructive healing and build tissue.

It is well understood that a functional ECM is critical for wound closure. Advances in modern regenerative medicine have provided tools such as Endoform that can be used to replace the patient’s missing or damaged ECM. These advanced technologies mimic the composition and structure of tissue ECM to act as a temporary functional ECM to resolve inflammation and support healing. As wound care practitioners, we are now in an era where we have a choice whether to simply manage wound symptoms or actively treat the underlying pathology with ECM technologies such as Endoform.