Bioengineered Platforms for Chronic Wound Infection Studies: How Can We Make Them More Human-Relevant?

Abstract

Chronic wound infections are an important cause of delayed wound healing, posing a significant healthcare burden with consequences that include hospitalization, amputation, and death. These infections most often take the form of three-dimensional biofilm communities, which are notoriously recalcitrant to antibiotics and immune clearance, contributing to the chronic wound state. In the chronic wound microenvironment, microbial biofilms interact closely with other key components, including host cellular and matrix elements, immune cells, inflammatory factors, signaling components, and mechanical cues. Intricate relationships between these contributing factors not only orchestrate the development and progression of wound infections but also influence the therapeutic outcome. Current medical treatment for chronic wound infections relies heavily on long-term usage of antibiotics; however, their efficacy and reasons for failure remain uncertain. To develop effective therapeutic approaches, it is essential to better understand the complex pathophysiology of the chronic wound infection microenvironment, including dynamic interactions between various key factors. For this, it is critical to develop bioengineered platforms or model systems that not only include key components of the chronic wound infection microenvironment but also recapitulate interactions between these factors, thereby simulating the infection state. In doing so, these platforms will enable the testing of novel therapeutics, alone and in combinations, providing insights toward composite treatment strategies. In the first section of this review, we discuss the key components and interactions in the chronic wound infection microenvironment, which would be critical to recapitulate in a bioengineered platform. In the next section, we summarize the key features and relevance of current bioengineered chronic wound infection platforms. These are categorized and discussed based on the microenvironmental components included and their ability to recapitulate the architecture, interactions, and outcomes of the infection microenvironment. While these platforms have advanced our understanding of the underlying pathophysiology of chronic wound infections and provided insights into therapeutics, they possess certain insufficiencies that limit their clinical relevance. In the final section, we propose approaches that can be incorporated into these existing model systems or developed into future platforms developed, thus enhancing their biomimetic and translational capabilities, and thereby their human-relevance.

Keywords: bioengineered platforms; biofilms; chronic wounds; ex vivo; in vitro; wound infection; wound models.

Figure 1

The PUBMED search tool was used to find relevant keywords in the title or main body of the article. For example, quotes were used to search for “chronic wounds” as a single term. Further, the AND operation was used to search for papers that had both “chronic wounds” as a term and the word biofilms. A similar strategy was used for all the other searches.

Figure 2

(A) Typical representation of the chronic wound bed microenvironment. (B) Key features of the chronic wound bed-capillary interface. From a bioengineering standpoint, the microenvironment can be represented by a two-compartment system, where the upper compartment consists of the “infected wound bed” with host cells, matrix and microbial biofilms and the lower compartment represents the capillary interface (endothelial cells) with immune components. (C) A simplified representation of key interactions between chronic wound biofilms and other key components of the chronic wound microenvironment, which can be suitably dissected on human-relevant bioengineered platform.