Descriptive vs mechanistic scientific approach to study wound healing and its inhibition: Is there a value of translational research involving human subjects?

Abstract

The clinical field of wound healing is challenged by numerous hurdles. Not only are wound-healing disorders complex and multifactorial, but the corresponding patient population is diverse, often elderly and burdened by multiple comorbidities such as diabetes and cardiovascular disease. The care of such patients requires a dedicated, multidisciplinary team of physicians, surgeons, nurses and scientists. In spite of the critical clinical need, it has been over 15 years since a treatment received approval for efficacy by the FDA in the United States. Among the reasons contributing to this lack of effective new treatment modalities is poor understanding of mechanisms that inhibit healing in patients. Additionally, preclinical models do not fully reflect the disease complexity of the human condition, which brings us to a paradox: if we are to use a "mechanistic" approach that favours animal models, we can dissect specific mechanisms using advanced genetic, molecular and cellular technologies, with the caveat that it may not be directly applicable to patients. Traditionally, scientific review panels, for either grant funding or manuscript publication purposes, favour such "mechanistic" approaches whereby human tissue analyses, deemed "descriptive" science, are characterized as a "fishing expedition" and are considered "fatally flawed." However, more emerging evidence supports the notion that the use of human samples provides significant new knowledge regarding the molecular and cellular mechanisms that control wound healing and contribute to inhibition of the process in patients. Here, we discuss the advances, benefits and challenges of translational research in wound healing focusing on human subject research.

Preclinical evaluation of a novel silver gelling fiber dressing on Pseudomonas aeruginosa in a porcine wound infection model

“…4,15,[25][26][27][28] Importantly porcine skin heals primarily by epithelialization similarly to human skin. 4,25,29,30 Wound Rep Reg (2019) 27 360-365 © 2019 by the Wound Healing Society This study shows that GFD Ag + treatment resulted in P. aeruginosa biofilm reduction and detachment of the biofilm from the porcine wound. In addition, wounds treated with GFD with and without Ag + showed more granulation tissue formation during early stages of wound healing process.…”

“…Porcine models are more relevant as pig skin is similar to human skin compared to rodent models, particularly in relation to epidermal‐dermal thickness ratios, dermal collagen, and elastic contents, similar patterns of hair follicles, blood vessels, and physical and molecular responses to various growth factors . Importantly porcine skin heals primarily by epithelialization similarly to human skin …”

A bioengineered living cell construct activates metallothionein/zinc/MMP8 and inhibits TGFβ to stimulate remodeling of fibrotic venous leg ulcers

“…Second, the lack of animal models that accurately recapitulate the complex features of chronic VLUs found in patients limits our ability to validate our findings at the mechanistic level. 25,41 Third, limitations in our clinical trial design did not allow for prospective validation of findings. Instead, future studies are needed to track and correlate the genomic indicators of the pro-healing, antifibrotic response identified in the VLU bed in this trial with clinical progression and outcomes in VLU, for their utilization as biomarkers during the process of VLU closure.…”

“…The BLCC construct disappears within 1–2 weeks, yet its clinical efficacy is evident months after application, suggesting that irrespective of whether its initial influences were direct, it must affect a sustained response that is perpetuated by resident VLU cells to lead to wound closure. Second, the lack of animal models that accurately recapitulate the complex features of chronic VLUs found in patients limits our ability to validate our findings at the mechanistic level . Third, limitations in our clinical trial design did not allow for prospective validation of findings.…”

Healing Chronic Wounds: Current Challenges and Potential Solutions

“…Thus, in this multifactorial system there is no one specific target point for intervention. Similarly, it is challenging to replicate it in animal model systems and to study the mechanisms that contribute to such complex pathology [18]. …”