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Review
. 2021 Aug;10(8):415-435.
doi: 10.1089/wound.2019.1143. Epub 2020 Oct 28.

Wound Healing Driver Gene and Therapeutic Development: Political and Scientific Hurdles

Xin Tang  1 , Michelle Hao  1 , Cheng Chang  1 , Ayesha Bhatia  1 , Kathrine O'Brien  1 , Mei Chen  1 , David G Armstrong  2 , Wei Li  1
Affiliations
Review

Wound Healing Driver Gene and Therapeutic Development: Political and Scientific Hurdles

Xin Tang et al. Adv Wound Care (New Rochelle). 2021 Aug.

Abstract

Significance: Since the last Food and Drug Administration (FDA) approval of a wound healing therapeutic in 1997, no new therapeutic candidate (excluding physical therapies, devices, dressings, and antimicrobial agents) has advanced to clinical applications. During this period, the FDA drug approvals for tumors, which have been referred to as "wounds that do not heal," have reached a total of 284 (by end of 2018). Both political and scientific factors may explain this large discrepancy in drug approvals for the two seemingly related and equally complex pathophysiological conditions. Recent Advances: Using the current research funding ratio of 1:150 for wound healing to cancer and the 5% FDA drug approval rate for oncology, we reach a crude estimate of a 0.03% success rate for wound healing therapeutics. Unless a drastic improvement of the current situation, we express a pessimistic outlook toward new and effective wound healing drugs. Critical Issues: We argue that successful development of wound healing therapeutics will rely on identification of wound healing driver genes (WDGs), and the focus should be on WDGs for the wound closure phase of wound healing. Therefore, WDGs must be both necessary and sufficient for wound closure; the absence of a WDG disrupts wound closure, while its supplementation alone is sufficient to restore full wound closure. Successful translation of a WDG into therapeutics requires availability of well-defined animal models with a high degree of relevance to humans. This review discusses the main hurdles faced by the wound healing research community behind the development of so-called "rescuing drugs" for wound healing. Future Directions: Given the lack of new wound healing drugs for the past 23 years, there is a need for a wide range of fresh, innovative, and thorough debates on wound healing drug development, including an organized movement to raise public support for wound healing research.

Keywords: Hsp90; growth factors; necessity and sufficiency; therapeutic; wound closure; wound healing driver gene.

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Conflict of interest statement

Authors claim no competing financial interests. All contents of this article were constructed and written by the authors listed. There were absolutely no ghostwriters used for the writing.

Figures

None
David G. Armstrong, DPM, MD, PhD
None
Wei Li, PhD
Figure 1.
Figure 1.
Pathology of wound healing and tumor progression. When the normal wound healing process becomes derailed by various systemic pathological conditions, the healing process may either be inhibited (left) or overactivated (right) leading to scarring and fibrosis. Tumors organize and utilize a similar “wound” microenvironment to support growth, invasion, and metastasis. Both processes share many common mechanisms and similar degrees of complexity.
Figure 2.
Figure 2.
Chart of LOA from highest to lowest by disease area. This figure is from the original fig. 2 of the report “Clinical Development Success Rates 2006–2015” by Thomas et al. and adapted with the authors' permission. The “wound healing” as a disease area and the complexity bar were added by authors of this article. From an LOA of 26.1% in hematology to 5.1% in oncology, there seems to be a negative correlation between success rate and disease complexity. Since the complexity of wound healing is equivalent to that of tumor progression, but the ratio of NIH funding for cancer research versus wound healing research is 150:1, the projected success rate of wound healing drugs is close to zero. LOA, likelihood of approval.
Figure 3.
Figure 3.
Requirements for a WDG candidate before drug development. (1) Genetic studies of the gene indicate necessity; (2) the correction of delayed wound closure by gene product supplementation alone in various animal models suggests sufficiency; (3) rapid accumulation of the gene product in the wound bed in response to wound stress signals, especially ischemia; (4) directional migration of the wound-surrounding cells, including immune cells, toward the wounded area must precede first for wound closure; and (5) the newly released WDG(s) must be functionally stable and minimally affected by the hazardous wound environment. WDG, wound healing driver gene.
Figure 4.
Figure 4.
Three hurdles facing growth factor therapy. The three major skin cell types, keratinocytes, dermal fibroblasts, and endothelial cells, involved in wound healing are indicated. An example of a conventional growth factor, PDGF-BB, is as shown. Growth factors face three major hurdles, which prevent them from being primary drivers of wound closure: (1) only selective cell type(s) express the cognate receptor; (2) growth factors are sensitive to the antiproliferation and antimigration effects of TGFβ3, and (3) their efficacy is compromised under pathological conditions. PDGF-BB, platelet-derived growth factor-BB; TGFβ3, transforming growth factor-beta3.
Figure 5.
Figure 5.
Comparison of wound closure rates among three types of commonly used wounds in mice. (A) A schematic illustration of three types of commonly used full-thickness excision wounds in mouse models. (B) Images of 8 mm wounds closing over time (data of a representative experiment, scale bar, 1 cm, taken from the supplementary fig. 2s of Ref. with permission of all authors of the publication). Arrows point corresponding wound methods used.
Figure 6.
Figure 6.
(A–D) Comparison among human, pig, rat, and mouse skin. Paraffin skin sections from healthy humans, pigs, rats, and mice are simultaneously subjected to H&E staining for structural comparisons. Images from the four species are shown with the same magnification scale. The measurement bars are as indicated (taken with permission of all the authors for Ref. 94 ). AP, apocrine (sweat) gland; BV, blood vessel; DM, dermis; EP, epidermis; H&E, hematoxylin and eosin; HF, hair follicle; M, muscle; SB, sebaceous gland.
Figure 7.
Figure 7.
Wounds on the same side of a pig torso heal with variable rates. (A, C) Comparison for wound closure rates (2.0 × 2.0 cm full-thickness wounds created on the same side of a pig 2.0 cm apart) between top and bottom wounds (A, a–d) and between middle and rear wounds (C, e–h). (B, D) A schematic presentation of left and right side of a pig with wounds at corresponding positions (wit same color). (E) Comparison of wound closure between two wounds on opposite sides (i vs. j on day 0 and k vs. l on day 14), but exactly the corresponding spots of the same pig (B, D) (e.g., W #5 vs. W′ #5) (taken with permission of all the authors for Ref. 94).
Figure 8.
Figure 8.
Duration of hyperglycemia correlates with degree of delay in wound closure in STZ-treated pigs. The delay in wound closure was examined in pigs injected with STZ 20, 45, and 90 days before wound surgery. (A) Effectiveness of STZ on insulin-producing cells in pancreas. (B) A pig 45 days after STZ injection. (C) Images of the 1.5 × 1.5 cm full-thickness wounds made in a normal pig; (D) images of wound closure in a pig 20 days after STZ injection; (E) images of wounds in a pig 45 days after STZ injection; (F) images of wounds in a pig 90 days after STZ injection (taken with permission of all the authors for Ref. 94). (a–n) represent average wound closure. Arrows indicate open wounds. STZ, streptozotocin.
Figure 9.
Figure 9.
A model of how secreted Hsp90 promotes reepithelialization and recruits dermal cells into the wound bed during wound closure. (Step 0) Uninjured intact skin with little detectable TGFβ3, cell migration, or stress; (Step 1) injury triggers release of TGFβ3, an immediate immotile to motile transition of keratinocytes and release of conventional growth factors. Growth factors are not able to recruit dermal cells to the wound bed due to the presence of TGFβ3; (Step 2) stressed keratinocytes at the wound edge release/secrete Hsp90α (round dots). Secreted Hsp90α reaches the threshold concentration of >0.1 μM and drives inward migration of dermal cells; (Step 3) keratinocyte migration closes the wound, TGFβ3 disappears, and the migrated dermal cells start to remodel the wound (taken with permission of all the authors for Ref. 90). Hsp90, heat shock protein-90.
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