Expert Opinion on Drug Discovery ISSN: 1746-0441 (Print) 1746-045X (Online) Journal homepage: https://www.tandfonline.com/loi/iedc20 The discovery and development of topical medicines for wound healing E. Öhnstedt, H. Lofton Tomenius, E. Vågesjö & M. Phillipson To cite this article: E. Öhnstedt, H. Lofton Tomenius, E. Vågesjö & M. Phillipson (2019) The discovery and development of topical medicines for wound healing, Expert Opinion on Drug Discovery, 14:5, 485-497, DOI: 10.1080/17460441.2019.1588879 To link to this article: https://doi.org/10.1080/17460441.2019.1588879 © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 14 Mar 2019. Submit your article to this journal Article views: 749 View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iedc20 EXPERT OPINION ON DRUG DISCOVERY 2019, VOL. 14, NO. 5, 485–497 https://doi.org/10.1080/17460441.2019.1588879 REVIEW The discovery and development of topical medicines for wound healing E. Öhnstedta,b, H. Lofton Tomeniusa,b, E. Vågesjöb and M. Phillipsona,b aDepartment of Medical Cell Biology, Uppsala University, Uppsala, Sweden; bIlya Pharma AB, Dag Hammarskiölds väg, Uppsala, Sweden ABSTRACT ARTICLE HISTORY Introduction: Chronic, nonhealing skin wounds claim >3% of the health-care budget in industrialized Received 19 November 2018 countries, and the incidence is rising. Currently, two parallel trends influence innovations within the Accepted 26 February 2019 field of wound healing: the need to reduce spread of antibiotic resistance and the emerging use of KEYWORDS health economy and value-based models. Chronic nonhealing wounds; Areas covered: This review focuses on the discovery of drug candidates and development of treat- chemokines; growth factors; ments aiming to enhance wound healing in the heterogeneous group of patients with nonhealing immune cells; clinical trials; wounds. active wound care Expert opinion: Nonhealing wounds are multifaceted and recognized as difficult indications. The majority of products currently in use are medical device dressings, or concepts of negative pressure or hyperbaric oxygen treatment. Global best practice guidelines for the treatment of diabetic foot ulcers recommend debridement, redressing, as well as infection control, and are critical to the lack of coherent clinical evidence for many approved products in active wound care. To accelerate wound healing, there is an emerging trend toward biologics, gene therapy, and novel concepts for drug delivery in research and in the pipeline for clinical trials. Scientific delineation of the therapeutic mechanism of action is, in our opinion, vital for clinical trial success and for an increased fraction of medical products in the pharmaceutical pipeline. 1. Introduction discomfort, pain, and increased risk for amputation, but are also associated with substantial health-care costs. Wound care is The skin forms a physical barrier crucial for protection against divided into different treatment types depending on its purpose microbial invasions, as well as maintaining temperature and (Figure 1): traditional, advanced, and active wound care. fluid homeostasis. Skin wounds transiently destroy this barrier, Traditional wound care is applied on acute wounds and only and thereby comprise a great health challenge. Historically, aims to cover and protect the wounds. If the wounds fail to heal, skin wounds were the major cause of gangrene and of septic advanced wound care in the form of dressings is used to keep death [1]. Understandably, treatments intending to improve wounds moist. For the last segment of nonhealing wounds, active healing of such skin wounds have a long history. Lowering of wound care aims at accelerated healing. According to a recently wound pH is acknowledged to counteract wound infections published systematic review of studies from all continents with and accelerate wound healing and was first mentioned by the majority from the USA, the annual mean cost for a nonhealing Hippocrates who recommended vinegar to clean the wounds wound was established to be $23 300 per afflicted patient ranging before applying dressings in the form of fig leaves [2]. Current from $1800 to $61,500 [4]. In Europe, the prevalence for nonheal- drug development, aiming to accelerate wound healing, often ing wounds is estimated between 1% and 2%, and associated total finds inspiration in the past. For instance, herbs used to heal costs thereby become extensive [5–8]. wounds within traditional Ayurvedic medicine are today being screened scientifically in the hunt for active substances, but presently those substances available in the clinic. 1.1. Wound healing Wounds can be divided into acute and nonhealing chronic Wound healing is a complex process characterized by dynamic wounds depending on the time to healing. If the wounds do not changes of the wound microenvironment to recruit and direct heal within 3 months, they are referred to as chronic, nonhealing the different participating cell types. The entire process is wounds. Nonhealing wounds are often coupled to underlying classically divided in four consecutive and overlapping phases: pathologies associated with reduced healing abilities (as in per- hemostasis, inflammation, proliferation, and remodeling sons with arterial or venous insufficiencies or persons having (Figure 1)[9,10]. During the hemostasis phase, the bleeding diabetes or receiving systemic steroid treatment) and/or increased is controlled by sympathetic-induced vasoconstriction fol- susceptibility for acquiring wounds (e.g. peripheral neuropathies) lowed by clot formation [10,11]. Cells of wounded tissue [3]. Patients developing nonhealing wounds form a heteroge- release alarm signals, chemokines, and growth factors that neous group, and nonhealing wounds are commonly divided recruit immune cells from blood circulation and stimulate into pressure ulcers, venous leg ulcers, arterial ulcers, and diabetic the proliferation of tissue resident populations, resulting in foot ulcers (DFUs). Nonhealing wounds do not only cause CONTACT M. Phillipson [email protected] Department of Medical Cell Biology, Uppsala University, Husargatan 3, P.O. Box 571, Uppsala 751 23, Sweden © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 486 E. ÖHNSTEDT ET AL. epithelialization was reported and resulted in impaired Article highlights wound healing [21]. However, extended presence of neutro- phils is a characteristic of nonhealing wounds, and another ● Development of topical drugs for wound healing is today greatly influenced by the need to reduce spread of antibiotic resistance and study revealed that wound healing was accelerated when the emerging emphasis of health economy neutrophils were depleted at the time of wound induction ● Topical drugs require means to ensure sufficient bioavailability of the but restored in overall numbers 5 days later [22]. Increasing active substance within the wound by, for example, onsite produc- tion and/or reduced degradation age clearly delays wound healing, and a mouse study demon- ● There is growing trend toward biologics, gene therapy, and novel strated that wound closure in young mice (2 months of age) concepts for drug delivery in drug discovery and in the pipeline for occurs independently of neutrophils, whereas older mice (6, clinical trials ● Increased understanding of the pathology of nonhealing wounds as 10, and 20 months) healed even slower when depleted of well as the mechanism of action of drug candidates are vital for neutrophils [23]. Depletion protocols target all neutrophils, success in clinical trials and thereby preclude studies addressing the importance of ● The increasing knowledge of multiple functions of immune cells in wound healing is likely to reveal novel targets. distinct populations with different functions. For instance, a proangiogenic neutrophil population was recently discovered This box summarizes key points contained in the article. and is recruited from blood circulation to tissue by vascular endothelial growth factor-A (VEGF-A) [24,25]. These neutro- phils are very likely to induce angiogenesis during the granu- lation phase, acting in parallel to classic neutrophils with immune cell accumulation at the wound site [12,13]. The important bactericidal effects during an interrupted skin proliferation phase is characterized by the formation of gran- barrier. ulation tissue that consists of newly formed blood vessels, Macrophages are important in wound healing as they pro- immune cells, and fibroblasts, and allows epidermal cell migra- duce many factors that drive the different phases of the healing tion on top of this tissue during re-epithelialization of the cascade (Figure 2). During the wound healing process, the wound. To strengthen the repaired tissue, fibroblasts in the macrophages shift phenotype from pro-inflammatory to a dermis and epidermis deposit new extracellular matrix during more regulatory phenotype with tissue restorative functions. the remodeling