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Oxygen, pH, Lactate, and Metabolism for Wound Treatment
Over time, we have come to recognize a very complex network of physiological changes enabling wound healing. An immunological process allows the body to distinguish damaged cells and begin a cleaning mechanism by separating damaged proteins and cells with matrix metalloproteinases, a complement reaction, and free radicals. A wide variety of cell functions help to rebuild new tissue, dependent on energy provision and oxygen supply. Topically applied lactate can improve this.
The prolonged healing of wounds remains an unresolved challenge in modern medicine. Although wounds exhibiting prolonged healing are primarily minor, they have a substantial social impact and influence the patient’s social status, daily living, and professional outcomes. Las Heras et al.  estimated 40 million chronic wounds worldwide, and the global wound market is predicted to reach USD 27.8 billion in 2026. The reasons given are the growing prevalence of chronic and surgical wounds as well as burn wounds. Cost-driving components include the increasing use of advanced wound care products, often as first-line therapies, where the advantages of these products over conventional treatment are the driving forces in the market . The advantages may range from greater patient comfort to easier usability. However, the effectiveness of many methods is still questionable, as there may be underlying conditions for the chronification of wounds. Diabetes, frailty, or vascular or immunological diseases even may affect burn wounds . Chronicity in burn wounds is a neglected topic, but Saaiq reported the incidence of Majolins ulcers as between 0.77 and 2%, primarily deriving from the healing per second intention .
Furthermore, the mortality of patients with chronic wounds rivals that of cancer patients , and the projected outpatient costs range from USD 9.9 to 35.8 billion, as outpatient treatment is a favored modality . In their paper “Publicly Reported Wound Healing Rates: The Fantasy and the Reality,” Fife et al. reported real-world data from randomized controlled trials and from the US Wound Registry that are prone to several risk-stratified quality measures. The conclusion was that RCTs (Randomized Controlled Trials) and US Wound Registry data provided convincing evidence that most wounds did not heal at all, but providers reported online healing rates over healing times that could only be qualified as impossible . Thus, the costs are rising, but the treatment success is stalling.
2. Wound Healing
The provisional matrix, composed of fibrin, plasma FN (fibronectin), vitronectin, and platelets, is in contact with migrating keratinocytes of the basal layer on the basal membrane . Initially, migrating epidermal cells find their way between the fibrin clot and the collagen-rich dermis. Thus, the matrix enables cell migration and promotes proto-myofibroblast contraction.
The proliferative and regenerative phase is characterized by fibroblast migration, collagen synthesis, angiogenesis, granulation tissue formation, re-epithelialization, protrusions developing cell–cell junctions, adhesion by integrins, and traction to the substratum . Different cytokines and growth factors such as PDGF, IGF-1, IL- 1β, IL-8, interferon-gamma (IFN-γ), SDF-1, and TNF-α are chemotactic for BMSCs (bone marrow-derived stem cells) and HFSCs (hair-follicle-derived stem cells). MSCs (mesenchymal stem cells) develop immunosuppressive and anti-inflammatory effects, remodel the ECM, and increase angiogenesis and cell differentiation.
The healing cycle is initiated by the activation of keratinocytes induced by the release of interleukin-1, upregulating the release of K6, K16, and K17 keratins, which might increase the viscoelastic properties and enable cell migration , making the keratinocytes contractile, and cause shrinkage of the provisional basement membrane. Activation starts within 24 h upon the change of the keratinocytes to an activated status. Interferon-γ from lymphocytes induces the expression of K17, enabling contractility . According to Safferling et al. , keratinocytes move in a shield extension mechanism for a multilayered epithelium, where suprabasal cells never come into contact with the ECM. In the coordination and overlapping of proliferation and migration, epithelium extends and closes the wounds. Basal keratinocytes are deactivated, dermal–epidermal junctions reappear, and hemidesmosomes anchor.
Collagen maturation during the remodeling phase can take 6 to 24 months . The initial collagen matrix comprises 30% collagen type 3, while intact tissue contains 10–20% collagen type 3 and 80–90% collagen 1 . Collagenases and proteases degrade these early fibrils, and this process is paralleled by collagen deposition. Crosslinking mediated by lysyl oxidase increases the thickness and stiffness, and the ratio of collagen 1 and collagen 2 is nearly the same as that for intact connective tissue. Twenty-eight different collagens have been identified in vertebrates; collagens II, III, V, and XI are fibril-forming collagens, while collagen I is the prevalent form in fibrotic conditions. As an essential part of normal wound healing, shrinking is mediated by myofibroblasts, which are generated under the influence of TGF-β. The differentiation into myofibroblasts largely depends on LDH and lactic acid, seems to be pH-dependent, and can be inhibited by gossypol, which inhibits LDH activity .
3. Current Insights
3.1. MMPs and Biofilms
3.2. Correcting the pH:
3.3. Improving Hypoxia and Lactate Accumulation
This entry is adapted from 10.3390/medicina57111190
- Las Heras, K.; Igartua, M.; Santos-Vizcaino, E.; Hernandez, R.M. Chronic wounds: Current status, available strategies and emerging therapeutic solutions. J. Control. Release 2020, 328, 532–550.
- The Global Wound Care Market is Projected to Reach USD 27.8 n.d. Available online: https://www.globenewswire.com/en/news-release/2021/04/29/2219343/0/en/The-global-wound-care-market-is-projected-to-reach-USD-27-8-billion-by-2026-from-USD-19-3-billion-in-2021-at-a-CAGR-of-7-6.html (accessed on 30 July 2021).
- Burn Wound Chronicity Myth or Reality-Wounds International. Jacky Edwards n.d. Available online: https://www.woundsinternational.com/resources/details/burn-wound-chronicity-myth-reality (accessed on 18 August 2021).
- Saaiq, M. Marjolin’s ulcers in the post-burned lesions and scars. World J. Clin. Cases 2014, 2, 507.
- Sen, C.K. Human Wounds and Its Burden: An Updated Compendium of Estimates. Adv. Wound Care 2019, 8, 39–48.
- Fife, C.E.; Eckert, K.A.; Carter, M.J. Publicly Reported Wound Healing Rates: The Fantasy and the Reality. Adv. Wound Care 2018, 7, 77–94.
- Clark, R.A.F.; Lanigan, J.M.; DellaPelle, P.; Manseau, E.; Dvorak, H.F.; Colvin, R.B. Fibronectin and Fibrin Provide a Provisional Matrix for Epidermal Cell Migration During Wound Reepithelialization. J. Investig. Dermatol. 1982, 79, 264–269.
- Pakyari, M.; Farrokhi, A.; Maharlooei, M.K.; Ghahary, A. Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing. Adv. Wound Care 2013, 2, 215–224.
- Velnar, T.; Bailey, T.; Smrkolj, V. The wound healing process: An overview of the cellular and molecular mechanisms. J. Int. Med. Res. 2009, 37, 1528–1542.
- Rousselle, P.; Braye, F.; Dayan, G. Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies. Adv. Drug Deliv. Rev. 2019, 146, 344–365.
- Freedberg, I.M.; Tomic-Canic, M.; Komine, M.; Blumenberg, M. Keratins and the keratinocyte activation cycle. J. Investig. Dermatol. 2001, 116, 633–640.
- Safferling, K.; Sütterlin, T.; Westphal, K.; Ernst, C.; Breuhahn, K.; James, M.; Jäger, D.; Halama, N.; Grabe, N. Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models. J. Cell. Biol. 2013, 203, 691–709.
- Saunders, R.; Astifidis, R.P.; McClinton, M.A. Hand and Upper Extremity Rehabilitation, 4th ed.; Elsevier: Amsterdam, The Netherlands, 2016.
- Broughton, G.; Janis, J.E.; Attinger, C.E.; Broughton, I.I.G.; Janis, J.E.; Attinger, C.E.; Christopher, E.M.D. The basic science of wound healing. Plast. Reconstr. Surg. 2006, 117, 12S–34S.
- Judge, J.L.; Lacy, S.H.; Kub, W.-Y.; Owensb, K.M.; Hernadya, E.; Thatcher, T.H.; Williams, J.P.; Phipps, R.P.; Sime, P.J.; Kottmann, R.M. The Lactate Dehydrogenase Inhibitor Gossypol Inhibits Radiation-Induced Pulmonary Fibrosis. Radiat. Res. 2017, 188, 35–43.
- Fields, G.B. The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma. Cells 2019, 8, 984.
- Greener, B.; Hughes, A.A.; Bannister, N.P.; Douglass, J. Proteases and pH in chronic wounds. J. Wound Care 2005, 14, 59–61.
- Kaufman, T.; Eichenlaub, E.H.H.; Angel, M.F.F.; Levin, M.; Futrell, J.W.W. Topical acidification promotes healing of experimental deep partial thickness skin burns: A randomized double-blind preliminary study. Burns 1985, 12, 84–90.
- Strohal, R.; Mittlböck, M.; Hämmerle, G. The Management of Critically Colonized and Locally Infected Leg Ulcers with an Acid-Oxidizing Solution: A Pilot Study. Adv. Skin Wound Care 2018, 31, 163–171.
- Smith, R.F.; Blasi, D.; Dayton, S.L.; Chipps, D.D. Effects of sodium hypochlorite on the microbial flora of burns and normal skin. J. Trauma Inj. Infect. Crit. Care 1974, 14, 938–944.
- Silvetti, A.N. An Effective Method of Treating Long-Enduring Wounds and Ulcers by Topical Applications of Solutions of Nutrients. J. Dermatol. Surg. Oncol. 1981, 7, 501–508.
- Hunt, T.K.; Aslam, R.; Hussain, Z.; Beckert, S. Lactate, with oxygen, incites angiogenesis. Adv. Exp. Med. Biol. 2008, 614, 73–80.
- Trabold, O.; Wagner, S.; Wicke, C.; Scheuenstuhl, H.; Hussain, M.Z.; Rosen, N.; Seremetiev, A.; Becker, H.D.; Hunt, T.K. Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 2003, 11, 504–509.
- Rendl, M.; Mayer, C.; Weninger, W.; Tschachler, E. Topically applied lactic acid increases spontaneous secretion of vascular endothelial growth factor by human reconstructed epidermis. Br. J. Dermatol. 2001, 145, 3–9.
- Porporato, P.E.; Payen, V.L.; De Saedeleer, C.J.; Préat, V.; Thissen, J.-P.; Feron, O.; Sonveaux, P. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 2012, 15, 581–592.
- Trengove, N.J.; Stacey, M.C.; Macauley, S.; Bennett, N.; Gibson, J.; Burslem, F.; Murphy, G.; Schultz, G. Analysis of the acute and chronic wound environments: The role of proteases and their inhibitors. Wound Repair Regen. 1999, 7, 442–452.
- Schultz, G.; Mozingo, D.; Romanelli, M.; Claxton, K. Wound healing and TIME; new concepts and scientific applications. Wound Repair Regen. 2005, 13, S1–S11.
- Dunn, K.; Edwards-Jones, V. The role of ActicoatTM with nanocrystalline silver in the management of burns. Burns 2004, 30 (Suppl. S1), S1–S9.
- Ryssel, H.; Kloeters, O.; Germann, G.; Schäfer, T.; Wiedemann, G.; Oehlbauer, M. The antimicrobial effect of acetic acid-An alternative to common local antiseptics? Burns 2009, 35, 695–700.
- Kalinin, A.E.; Kajava, A.V.; Steinert, P.M. Epithelial barrier function: Assembly and structural features of the cornified cell envelope. BioEssays 2002, 24, 789–800.
- Leveen, H.H.; Falk, G.; Borek, B.; Diaz, C.; Lynfield, Y.; Wynkoop, B.J.; Mabunda, C.; Rubricius, I.; Ieanette, L.M.D.; Christoudias, G. Chemical acidification of wounds. An adjuvant to healing and the unfavorable action of alkalinity and ammonia. Ann. Surg. 1973, 178, 745–753.
- Ryssel, H.; Andreas Radu, C.; Germann, G.; Kloeters, O.; Riedel, K.; Otte, M.; Kremer, T. Suprathel-antiseptic matrix: In vitro model for local antiseptic treatment? Adv. Skin Wound Care 2011, 24, 64–67.
- Blome-Eberwein, S.A.; Amani, H.; Lozano, D.D.; Gogal, C.; Boorse, D.; Pagella, P. A bio-degradable synthetic membrane to treat superficial and deep second degree burn wounds in adults and children—4 year experience. Burns 2021, 47, 838–846.
- Braverman, I.M. The cutaneous microcirculation. J. Investig. Dermatol. Symp. Proc. 2000, 5, 3–9.
- Gürünlüoğlu, K.; Demircan, M.; Taşçı, A.; Üremiş, M.M.; Türköz, Y.; Bağ, H.G.; Akinci, A.; Bayrakçı, E. The Effects of Two Different Burn Dressings on Serum Oxidative Stress Indicators in Children with Partial Burn. J. Burn Care Res. 2019, 40, 444–450.
- McKelvey, K.; Jackson, C.J.; Xue, M. Activated protein C: A regulator of human skin epidermal keratinocyte function. World J. Biol. Chem. 2014, 5, 169–179.
- Gladden, L.B. Current Trends in Lactate Metabolism: Introduction. Med. Sci. Sports Exerc. 2008, 40, 475–476.
- Knighton, D.R.; Silver, I.A.; Hunt, T.K. Regulation of wound-healing angiogenesis-Effect of oxygen gradients and inspired oxygen concentration. Surgery 1981, 90, 262–270.
- Hunt, T.K.; Gimbel, M.; Sen, C.K. Revascularization of Wounds: The oxygen-Hypoxia Paradox. In Angiogenesis; Figg, W.D., Folkman, J., Eds.; Springer: Boston, MA, USA, 2008; pp. 541–559.
- Gladden, L.B. Lactate metabolism: A new paradigm for the third millennium. J. Physiol. 2004, 558, 5–30.
- Lee, D.C.; Sohn, H.A.; Park, Z.Y.; Oh, S.; Kang, Y.K.; Lee, K.M.; Kang, M.; Jang, J.Y.; Yang, S.-J.; Noh, H.; et al. A lactate-induced response to hypoxia. Cell 2015, 161, 595–609.
- Falanga, V.; Zhou, L.; Yufit, T. Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF-β1. J. Cell. Physiol. 2002, 191, 42–50.
- Reinke, J.M.; Sorg, H. Wound repair and regeneration. Eur. Surg. Res. 2012, 49, 35–43.
- Chatham, J.C. Lactate-The forgotten fuel! J. Physiol. 2002, 542, 333.
- Pastar, I.; Stojadinovic, O.; Yin, N.C.; Ramirez, H.; Nusbaum, A.G.; Sawaya, A.; Patel, S.B.; Khalid, L.; Isseroff, R.R.; Tomic-Canic, M. Epithelialization in Wound Healing: A Comprehensive Review. Adv. Wound Care 2014, 3, 445–464.
- Lu, Y.; Wahl, L.M. Oxidative Stress Augments the Production of Matrix Metalloproteinase-1, Cyclooxygenase-2, and Prostaglandin E 2 through Enhancement of NF-κB Activity in Lipopolysaccharide-Activated Human Primary Monocytes. J. Immunol. 2005, 175, 5423–5429.
- Marty, P.; Chatelain, B.; Lihoreau, T.; Tissot, M.; Dirand, Z.; Humbert, P.; Senez, C.; Secomandi, E.; Isidoro, C.; Rolin, G. Halofuginone regulates keloid fibroblast fibrotic response to TGF-β induction. Biomed. Pharmacother. 2021, 135, 111182.
- Nischwitz, S.; Popp, D.; Shubitidze, D.; Luze, H.; Haller, H.; Kamolz, L. The successful use of polylactide wound dressings for chronic lower leg wounds—A retrospective analysis. Int. Wound J. 2021, in press.
- Haller, H.L.; Blome-Eberwein, S.E.; Branski, L.K.; Carson, J.S.; Crombie, R.E.; Hickerson, W.L.; Kamolz, L.P.; King, B.T.; Nischwitz, S.P.; Popp, D.; et al. Porcine xenograft and epidermal fully synthetic skin substitutes in the treatment of partial-thickness burns: A literature review. Medicina 2021, 57, 432.