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Observations on the Remarkable (and Mysterious) Wound-Healing Process of the Bottlenose Dolphin

      TO THE EDITOR
      Healing of large traumatic soft-tissue wounds in humans is often associated with scarring and infection. Medical management involves initial antisepsis, hemostasis, control of infection, and attempts to control scar formation through surgical intervention. The treatment of microbially contaminated large soft-tissue wounds remains a medical challenge.
      I wish to call attention to the healing of deep soft tissues by the bottlenose dolphin (Indo-Pacific bottlenose dolphins, Tursiops sp.). Dolphins commonly sustain deep soft-tissue injuries from shark bites (
      • Celona A.
      • De Maddalena A.
      • Comaretto G.
      Evidence of a predatory attack on bottle nose dolphin Tursiops truncatus by a great white shark in the mediterranean sea.
      ). About 40% of bottlenose dolphins surveyed by one marine station in Australia appeared to have survived a shark bite, based on distinguishable surface markings (
      • Corkeron P.J.
      • Morris R.J.
      • Bryden M.M.
      Interactions between Bottlenose dolphins and Sharks in Moreton Bay, Quensland.
      ). In what manner does a deep wound heal in these mammals in the sea? Will an appreciation of the mechanism of repair provide new insights to those of us involved in the care of human injuries?
      Two case reports are presented that illustrate the types of injury I am referring to and the nature of the recovery process, derived from the observations and photographs shared with me by marine biologists caring for these severely wounded male dolphins (Supplemmentary Information online). The clinical course of the recovery of these individuals was consistent with the limited observations on dolphin wound healing that are published (
      • Bruce-Allen L.J.
      • Geraci J.R.
      Wound healing in the bottle nose dolphin.
      ;
      • Corkeron P.J.
      • Morris R.J.
      • Bryden M.M.
      A note on the healing of large wounds inthe bottle nose dolphins.
      ;
      • Bloom P.
      • Yeager M.
      The injury and subsequent healing of a serious propeller strike to a bottle nose dolphin resident in the cold waters off the Northumberland coast of England.
      ;
      • Orams M.B.
      • Deakin R.B.
      ), including the rate of wound healing, the eventual restoration of near normal body surface contour, and the apparent indifference to pain.
      The animals sustained several shark-inflicted wounds, each about 30cm in length and 3cm deep, extending completely through the blubber layer and sparing the underlying muscle. Within the first day after injury, blubber from the surrounding tissues had migrated over the open-wound surface, providing a white, cover-like dressing. Newly regenerating pink tissues (described as “granulation tissue”) were noted by the second day and appeared to gradually fill the wound upward from its base, eventually restoring the volume deficit with blubber. Non-viable tissues, including the transposed blubber, gradually debrided over the first week. The epidermis overlying the wound closed last. About 4 weeks after injury, the wounds had healed. All the while, despite the injury, their behavior did not appear to reflect pain, to such an extent that the caretakers took notice.
      Much about the dolphin's healing process remains unreported and poorly documented. By what mechanism is blood loss constrained? Surprisingly, the coagulation system of the bottlenose dolphin is poised to clot less readily than that of terrestrial mammals (
      • Tibbs R.F.
      • Elghetany M.T.
      • Tran L.T.
      • et al.
      Characterization of the coagulation system in healthy dolphins: the coagulation factors, natural anticoagulants, and fibrinolytics.
      ), likely an adaptation to the acidosis and diminished blood flow that accompanies diving (“diving reflex”). Might the initial trauma activate the diving reflex to divert blood from the periphery? The repair of large volume tissue deficits occurs through a process that ultimately restores the complex composite (and specifically organized) structure of blubber (
      • Pabst D.A.
      Springs in swimming animals.
      ), knitting the newly formed tissue with the existing fabric of adipocytes, collagen, and elastic fibers (Ann Pabst, personal communication); in this context, wound healing is more reminiscent of the regenerative repair process of the early gestation mammalian fetus than the uncoordinated scar-producing repair that characterizes soft-tissue healing in terrestrial mammals. The apparent indifference of the bottlenose dolphin to pain after extensive soft-tissue injury clearly represents an adaptation favorable for survival in the setting of the sea. The dolphin responds to painful stimuli (such as a needle prick) with protest/withdrawal movements, so we imagine that the dolphin has the capacity to feel pain in certain contexts (Sam Ridgway, personal communication). The neurological/physiological mechanisms engaged to reduce pain consciousness in the setting of traumatic soft-tissue injury are unknown.
      The absence of infection in the open wounds sustained by the dolphin continuously exposed to seawater is remarkable. The immune system of the dolphin appears to be similar to that of terrestrial mammals (
      • Mancia A.
      • Lundqvist M.L.
      • Romano T.A.
      • et al.
      A dolphin peripheral blood leukocyte cDNA microarray for studies of immune function and stress reactions.
      ), and thus an explanation is sought elsewhere. We turn to the blubber of this animal. The composition of this tissue has been studied extensively for many years because it accumulates many toxic pollutants of human origin, such as organohalogens and heavy metals, from its food sources, and permits us to monitor environmental pollution. In addition to “pollutants”, blubber contains organohalogens that are of natural origin (
      • Vetter W.
      • Scholz E.
      • Gaus C.
      • et al.
      Anthropogenic and natural organohalogen compounds in blubber of dolphins and dugongs (Dugong dugon) from northeastern Australia.
      ,
      • Vetter W.
      • Jun W.
      • Althoff G.
      Non-polar halogenated natural products bioaccumulated in marine samples. I. 2,3,3′,4,4′,5,5′-Heptachloro-1′-methyl-1,2′-bipyrrole (Q1).
      ,
      • Vetter W.
      • Jun W.
      Non-polar halogenated natural products bioaccumulated in marine samples. II. Brominated and mixed halogenated compounds.
      ). Although the origin of these non-human-derived compounds has not been identified, several resemble known substances that are produced by marine organisms, such as algae and plankton (). Organohalogens are known to exhibit antimicrobial properties, such as the inhibition of biofilm formation () and antibiotic activity (). One might imagine that under certain circumstances, for example, as the blubber tissue undergoes “decomposition” following trauma, some of these compounds could be released locally and could provide antimicrobial protection to the tissues within the immediate wound environment. Perhaps the very fact that this animal accumulates organohalogens to the extent it does in its blubber (rather than metabolize and excrete them) speaks to a natural mechanism designed to permit the animal to concentrate and store protective compounds from its food sources for its own use.
      The triglycerides that comprise dolphin blubber appear to differ from other marine mammals, including that of whales and seals by their uniquely high proportions of the short-chain fatty acid isovaleric acid (
      • Koopman H.N.
      • Iverson S.J.
      • Read A.J.
      High concentrations of isovaleric acid in the fats of odontocetes: variation and patterns of accumulation in blubber vs. stability in the melon.
      ). In a survey of blubber lipid composition conducted on a range of dolphin species and other marine mammals, the highest concentrations of isovaleric acid were found in Hector's dolphins where isovaleric acid represented about 50% (in terms of mole fraction) of the fatty acids of blubber, the bottlenose dolphin between 2–5%, and none detected in several species of whale (
      • Koopman H.N.
      • Iverson S.J.
      • Read A.J.
      High concentrations of isovaleric acid in the fats of odontocetes: variation and patterns of accumulation in blubber vs. stability in the melon.
      ). The isovaleric acid composition of the blubber varies with depth, higher in the blubber closer the skin than in deeper tissues. Isovaleric acid is believed to be synthesized de novo within blubber from branched-chain amino acids (
      • Budge S.M.
      • Iverson S.J.
      • Koopman H.N.
      Studying trophic ecology in marine ecosystems using fatty acids: a primer on analysis and interpretation.
      ). During periods of starvation, when blubber is utilized as an energy source, long-chain fatty acids are metabolized, whereas isovaleric acid appears to be conserved. Why the dolphin accumulates isovaleric acid in its blubber is unclear. A leading hypothesis proposes that isovaleric acid influences the physical compressibility of the fatty tissue in ways that enhance its acoustic properties (
      • Litchfield C.
      • Greenberg A.J.
      • Caldwell D.K.
      • et al.
      Comparative lipid patterns in acoustical and nonacoustical fatty tissues of dolphins, porpoises and toothed whales.
      ); another suggests that the high proportion of isovaleric acid reduces the freezing point of the blubber, thereby improving its utility as a thermal insulator (
      • Koopman H.N.
      • Iverson S.J.
      • Read A.J.
      High concentrations of isovaleric acid in the fats of odontocetes: variation and patterns of accumulation in blubber vs. stability in the melon.
      ).
      In the context of the role possibly played by blubber in the setting of injury, it is curious to note that isovaleric acid has antimicrobial activity and may well serve that function for other marine organisms. A recent report identified isovaleric acid as the major antimicrobial compound produced by the marine microorganism Pseudoalteromonas haloplanktis. Of particular interest was the demonstration that isovaleric acid exhibited a broad spectrum of antibacterial activity, including Gram-negative organisms such as Vibrio, Pseudomonas, and Aeromonas, species known to colonize and infect marine mammals (
      • Hayashida-Soiza G.
      • Uchida A.
      • Mori N.
      • Kuwahara Y.
      • et al.
      Purification and characterization of antibacterial substances produced by a marine bacterium Pseudoalteromonas haloplanktis strain.
      ). This leads me to suggest that isovaleric acid stored within blubber could serve an antimicrobial function, released from the tissue in the context of injury. It could serve to control local microbial growth within the surrounding tissues or function to preserve the damaged blubber itself from microbial decomposition. This hypothesis predicts that deep soft-tissue healing would be favored in those species of marine mammal invested with blubber containing higher concentrations of isovaleric acid.
      The bottlenose dolphin has been highlighted among other marine mammals in this report because of the larger body of experience with this species of animal, albeit incomplete with respect to wound healing. Injured free-ranging animals that regularly return to marine stations for feeding provide humans with the opportunity to observe the healing process. Reports of the survival after severe traumatic injury of other marine mammals, such as the southern elephant seal (
      • Van den Hoff J.
      • Morrice M.G.
      Sleeper shark (Somniosus antarcticus) and other bite wounds observed on southern elephant seals (Mirounga leonina) at Macquarie Island.
      ) and the Hawaiian monk seal (
      • Bertilsson-Friedman P.
      Distribution and frequencies of shark-inflicted injuries to the endangered Hawaiian monk seal (Monachus schauinslandi).
      ), suggest that efficient healing of soft-tissue injury might be widespread among marine mammals. The extent to which the healing process of other marine mammals, including other species of dolphin, resembles that of the bottlenose dolphin, represents an interesting area of inquiry.

      ACKNOWLEDGMENTS

      I acknowledge Trevor Hassard and his staff at the Marine Education and Conservation Centre of the Tangalooma Island Resort (Moreton Island, Australia) for generously providing me with the photographs of Echo and Nari, graciously sharing their clinical experience, and reviewing the manuscript; Trevor Long and Dr David Blyde (Sea World, Gold Coast, QLD, Australia) for reading early drafts of the manuscript; Phil Coulthard of the Dolphin Discovery Center (Bunbury, WA) for sharing his personal experience with the successful recovery of injured dolphins left to heal without human intervention; Dr Sam H. Ridgway (National Marine Mammal Foundation, San Diego, CA) for sharing his knowledge of dolphin sensory responses; Drs Leigh Clayton and Brent Whitaker (National Aquarium, Baltimore, MD) for their review of the manuscript; Dr Janet Mann (Georgetown University) for very early discussions of her experiences of injury among the dolphins she studies in the setting of her research on dolphin behavior; Dr Ann Pabst (University of North Carolina, Wilmington, NC) for sharing her knowledge of the structural characteristics of dolphin blubber; and Dr Walter Vetter (University of Hohenheim, Stuttgart, Germany) for review of my discussion on organohalogens in blubber.

      SUPPLEMENTARY MATERIAL

      Supplemmentary material is linked to the online version of the paper at http://www.nature.com/jid

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