Advanced Wound Diagnostics: Toward Transforming Wound Care into Precision Medicine

Abstract

Significance: Nonhealing wounds are an ever-growing global pandemic, with mortality rates and management costs exceeding many common cancers. Although our understanding of the molecular and cellular factors driving wound healing continues to grow, standards for diagnosing and evaluating wounds remain largely subjective and experiential, whereas therapeutic strategies fail to consistently achieve closure and clinicians are challenged to deliver individualized care protocols. There is a need to apply precision medicine practices to wound care by developing evidence-based approaches, which are predictive, prescriptive, and personalized. Recent Advances: Recent developments in "advanced" wound diagnostics, namely biomarkers (proteases, acute phase reactants, volatile emissions, and more) and imaging systems (ultrasound, autofluorescence, spectral imaging, and optical coherence tomography), have begun to revolutionize our understanding of the molecular wound landscape and usher in a modern age of therapeutic strategies. Herein, biomarkers and imaging systems with the greatest evidence to support their potential clinical utility are reviewed. Critical Issues: Although many potential biomarkers have been identified and several imaging systems have been or are being developed, more high-quality randomized controlled trials are necessary to elucidate the currently questionable role that these tools are playing in altering healing dynamics or predicting wound closure within the clinical setting. Future Directions: The literature supports the need for the development of effective point-of-care wound assessment tools, such as a platform diagnostic array that is capable of measuring multiple biomarkers at once. These, along with advances in telemedicine, synthetic biology, and "smart" wearables, will pave the way for the transformation of wound care into a precision medicine. Clinical Trial Registration number: NCT03148977.

Keywords: biomarkers; diagnostics; imaging; smart dressings; synthetic biology; wound healing.

Maximillian A. Weigelt, MD

Figure 1.

Estimated incidence of various subtypes of cancer versus nonhealing wounds in the United States. Some types of nonhealing wounds have higher incidence than some of the most common cancers, and nonhealing wounds overall are estimated to occur at a higher rate than cancer in general.^,

Figure 2.

Acute wound-healing responses—phases and cellular effectors. Normal wound healing proceeds through multiple distinct yet overlapping phases: coagulation, inflammation, migration/proliferation, and remodeling.

Figure 3.

Nonsequential progression toward wound closure; stalled, chronically inflamed wound bed in a venous ulcer. A derangement in any of the normal phases of wound healing can result in a nonhealing wound. Nonhealing wounds are frequently characterized by prolonged, deleterious inflammation, dysfunctional proliferation, and/or failed epithelialization.

Figure 4.

The chronic wound microenvironment. Chronic wounds are characterized by a prolonged, deleterious inflammatory state. Imbalance in pro-inflammatory cytokines, excessive proteolysis by MMPs, and various other cellular derangements prevent the timely and orderly restoration of the skin barrier. ECM, extracellular matrix; EGF, epidermal growth factor; EPC, endothelial progenitor cell; FGF, fibroblast growth factor; IL-1β, interleukin one beta; MMPs, matrix metalloproteases; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TNFα, tumor necrosis factor alpha; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.^,

Figure 5.

Relationship of biomarkers to physiologic wound healing. Overview of the role of pH and MMPs within the complex wound microenvironment. Some, but not all, important wound-healing cytokines and substrates are shown—those in orange, although necessary for physiologic healing, are commonly overexpressed in nonhealing wounds. MMPs and pH interplay intricately within the wound microenvironment in a phenomenon known as “dynamic reciprocity.” pH affects ECM synthesis, enzyme activity, cell cycle progression, oxygen delivery, fibroblast activity, and bacterial growth. The effects of MMPs are also manifold, as they are crucial for ECM remodeling and angiogenesis, cell migration, and cytokine regulation, though their overexpression results in poor wound healing. FGFR, fibroblast growth factor; HGF, hepatocyte growth factor; IL-X, interleukin X; KGF, keratinocyte growth factor; /R, receptor.^,

Figure 6.

A theoretical diagnostic platform for wound biomarkers. The current approach to wound appraisal and treatment is limited by the time cost of determining healing status, as well as the inability of available treatments to achieve consistent wound closure and provide personalized/precision therapies. A diagnostic platform with an array of wound biomarkers would theoretically allow for instant determination of wound status and facilitate tailoring of specific, individualized wound therapies.

Figure 7.

Connected “smart” dressings for wound care. As the wound care landscape continues to shift toward telemedicine, smart dressings have great potential to facilitate remote wound status monitoring. This could guide at-home wound care by providing instructions to patients or visiting clinicians, and determine the need for follow-up appointments. Smart dressings are also being engineered to deliver therapy in an automated fashion, which might include drug delivery (e.g., antimicrobials), pH modulation, and moisture balance.^,,,