University of Minnesota
University of Minnesota

Unit's name.

Areas of Research

Cardiac Function during Hibernation

The Effects and Potential Use for Hibernation Induction Trigger

Wound Healing

Wound Formation, Treatment, and Healing



Cardiac Function during Hibernation: EKG and Echocardiographic Analyses

Black bears (Ursus americanus) remain inactive during hibernation, during which time their body temperatures drop to approximately 4°C below normal and they do not eat, drink, urinate, or defecate. Yet, during this time, hibernating bears can return to apparently normal systemic function within minutes of arousal. The hearts of hibernating bears must be conservative in terms of energy expenditure, and must also be capable of supporting rapid arousal in the event of threats (i.e., predators). A reduction in cardiovascular function without adequate protection in large mammals (including humans) would, within hours, result in irreversible ischemic tissue damage.

Along with the Department of Natural Resources and Medtronic, Inc., our lab has studied the cardiovascular performance of hibernating bears in the wild. Implantable data recorders, echocardiography, and electrocardiography were used to show that cardiac mass and electrophysiology are conserved during hibernation [1]. A dramatic heart rate modulation from exceptionally low values (4.5 beats/min), accelerated by up to 865% during inspiration, minimizes energy expenditure while maintaining cardiac mass and adequate brain and tissue perfusion.

This adaptive cardiac physiology may have broad implications for human medicine (i.e., Seasonal Affective Disorder, heart failure, heart attack) and possibly space travel, since it would allow for prolonged periods of inactivity while maintaining both cardiac capacity and alertness.

1. Laske TG, Harlow HJ, Werder JC, Marshall MT, Iaizzo PA: High capacity implantable data recorders: system design and experience in canines and denning black bears. Journal of Biomechanical Engineering 127:964-971, 2005.


The Effects and Potential Use of Hibernation Induction Trigger (HIT)

Currently, many questions remain unanswered regarding the role of ∂-opioid agonists and/or hibernation factors in myocardial protection. First, it is still unclear whether opioid-mediated cardioprotection is mediated through ∂-1 or ∂-2 opioid receptors, which is considered important knowledge for the ultimate development of specific therapeutic drugs. Our laboratory has shown the potential of infarct-limiting effects of opioid preconditioning (∂-opioids or hibernation induction trigger protein). We found significant infarct size reductions with either δ-1 or δ-2 specific agonists in a porcine coronary occlusion model. Also, it has been shown that ischemic preconditioning may reduce apoptosis.

Sigg DC, Coles JA Jr, Gallagher WJ, Oeltgen PR, Iaizzo PA: Opioid preconditioning: myocardial function and energy metabolism.  The Annals of Thoracic Surgery, 72:1576-1582, 2001.

Sigg D, Coles JA Jr, Oeltgen P, Iaizzo PA: Role of delta-opioid receptors on infarct size reduction in swine.  American Journal of Physiology: Heart and Circulatory. 282:H1953-1960, 2002.

Sigg DC, Coles JA, Iaizzo PA: Surgical myocardial protection: Part II. From ischemic preconditioning to gene therapy: emerging experimental cardioprotective approaches.  In: Progress in Anesthesiology. Dannemiller Memorial Education Foundation, Volume XVI, Chapter 5, pages 63-80, 2002.

Laske TG, Harlow HJ, Garshelis DL, Iaizzo PA: Extreme respiratory sinus arrhythmia enables overwintering black bear survival—physiological insights and applications to human medicine. Journal of Cardiovascular Translational Research, 3:559-69, 2010.

Coles JA Jr, Sigg DC, Iaizzo PA: Role of kappa-opioid receptor activation in pharmacological preconditioning in swine. American Journal of Physiology: Heart and Circulatory, 284:2091-2099, 2003.


Wound Healing

Hibernating black bears (Ursus americanus) elicit profound abilities to resolve injuries while mildly hypothermic (30-35ºC) and not eating, drinking, urinating, or defecating. We continue to perform investigative studies on free-ranging black bears during denning in early winter and again in late winter. To date, three methods have been employed to induce small cutaneous wounds during three consecutive winters on 10 different bears, two of which were studied for more than one winter. Tissue samples were processed by routine histological methods and evaluated by light microscopy. All sites healed with remodeling of the dermal layers, reduced expression of scarring, and limited regrowth of hair. Even significant injuries that were incurred prior to hibernation, but which had not begun to heal at the time of hibernation, were completely resolved in 1-2 months. This unique healing ability is a clear survival advantage for bears, as those unable to heal while hibernating could suffer loss of body fluids, greatly increased metabolic demands, and/or toxicity from infection. Other hibernating mammals, however, appear to lack this ability. These observations may provide new insights, and further investigation may uncover new biological materials for treating wounds with little or no scarring in humans, especially in patients who are malnourished, hypothermic, diabetic, or elderly.

Figure 5. (a) Injury incurred before denning (Bear 2081), first observed in December (left) and after healing 12 weeks later (right). This animal’s core body temperature was 35.4°C in December and 32.8°C in March. (b) Paired infrared images from those shown in (a), with the temperature scale of 25°C (black) to 35°C (white). Subsequent to initial December photos (a, left), a local subcutaneous injection of lidocaine was administered along the injury border, the injury was debrided, and single sutures were used to close the skin edges (approximately 1 cm spacing). (c) Close-up view before (left) and after (center) suturing, as well as after a healing period (right). In the late winter photos (right), a small line of new hair can be detected (1–3 mm wide), just along the line where the skin was sutured.
Source: Iaizzo PA, Laske TG, Harlow HL, McClay CB, Garshelis DL: Wound healing during hibernation by black bears (Ursus americanas) in the wild: elicitation of reduced scar formation, Integrative Zoology, 7:48-60, 2012.


Wound Formation, Treatment, and Healing

The occurrence of pressure ulcers among the elderly and in hospitalized patients has an extensive impact on patients and health care providers in terms of decreased quality of life, loss of productivity, and high cost of treatment. Various studies indicate that 50-60% of all pressure ulcers in acute hospital populations develop after admission and thus are deemed preventable (i.e., more frequent risk assessment, treatment plans, specialty devices, etc.). Although extensive literature exists concerning pressure ulcers, there remains no clear consensus regarding the etiology of such wounds. Rather, several factors are known to contribute to the formation and persistence of pressure-related wounds, including elevated pressure over extended time, shear, elevated pressure augmented by elevated temperature, age, poor nutrition, incontinence, fractures, paralysis or lack of sensation, arterial insufficiency, venous stasis, and diabetes. Specifically, there are few detailed reports about the thresholds of wound formation with respect to pressure, temperature, and duration of application, and lack of clear consensus about the proper form of treatment. Clinicians use a variety of visual methods to evaluate the status of skin tissue, however these methods lack precision, and quantification of slow or subtle changes may be difficult. Accurate determination of the extent and depth of subsurface injuries would allow for appropriate and timely therapeutic intervention.


Related studies in our lab include the following:
• Development of a porcine model to facilitate investigation of pressure ulcer formation, healing, and prevention (Figures 1 and 2). This model allows for easy, independent modulation of pressure, temperature, and duration parameters to create specific classes of wounds [1].

• Investigation of the effects of duration of applied pressure and applied temperature on wound formation, as well as the threshold temperature below which focalized cooling will minimize the potential for wound formation using a porcine model. The benefits of focal cooling were evident at an extended duration and at deep tissue layers, and suggest future clinical applications for pressure ulcer prevention and therapy [2].

• Examination of the use of cutaneous reactive hyperemia as a means for noninvasive assessment of wound severity of newly formed temperature-modulated pressure injuries in a porcine model. This study employed color image analysis to determine the severity of wounds and infrared imaging/computer image processing to detect differences in skin temperature. Both techniques correlated with the severity of injuries as determined by a histologic assessment of biopsied tissue, however infrared imaging provided the better means to assess wound depth [3].

• Critical assessment of potential methodologies for noninvasive wound evaluation using a color imaging system, development of a method for quantifying histological readings, and testing these techniques on a porcine model of wound formation. Color analyses enabled statistically significant differentiation of mild, moderate, and severe injuries within 30 minutes after application of the injury, and again when the wounds were 5-7 days old; this technique could be adapted for assessing and tracking wound severity in humans in a clinical setting [4].

• Explicit definition of critical thresholds of applied pressure, duration, and temperature in the formation of pressure ulcers or cutaneous burns in a porcine model. Pathological changes in pressure ulcers were found to begin at the deep muscle and progress upward into the cutaneous layers with increasing pressure and/or duration of contact; muscle degeneration was also observed after 5 hours of ischemia (Figure 3). Thresholds for all four cutaneous layers increased with a decrease in applied temperature, suggesting that these deep tissue changes could be lessened or prevented with appropriate focal cooling. Such predictions of thresholds for injury causation could provide a predictive basis for the design and development of support surfaces and patient turning schedules for the prevention of tissue injury [5].

• Noninvasive assessment of the severity and depth of pressure injuries in dermal and subdermal tissue using infrared thermography in a porcine model. Two techniques were investigated: 1) thermographic evaluation of wounds at thermal equilibrium with normal room temperature surroundings, and 2) observation of temperature changes that occurred to the wound area after application of focal cooling. Deep tissue injuries were easily distinguished from shallow wounds by their thermal response to focal cooling, suggesting clinical utility for detecting abscessed areas of skeletal muscle that are concealed by a healthy epidermal or dermal bridge (6).

Figure 1. Cluster of 4 discs was designed to apply pressure to preselected wound sites. Temperature
modulation was facilitated with a micro-processor-controlled unit; cooling was provided by a water
bath and heating by electrical resistance wire. Temperatures were maintained within ±0.5°C.

Figure 2. Disc application and subsequent assessment sites

Figure 3. Illustrative representation of tissue damage at combinations of pressure,
temperature, and duration that resulted in tissue alterations

1. Kokate JY, Leland KJ, Held AM, Hansen GL, Kveen GL, Johnson BA, Wilke MS, Sparrow EM, Iaizzo PA: Temperature-modulated pressure ulcers: a porcine model. Archives of Physical Medicine and Rehabilitation, 76:666-673, 1995.
2. Iaizzo PA, Kveen GL, Kokate JY, Leland KJ, Hansen GL, Sparrow EM: Prevention of pressure ulcers by focal cooling: histological assessment in a porcine model. Wounds: A Compendium of Clinical Research and Practice, 7:161-169, 1995.
3. Hansen GL, Sparrow EM, Kammamuri R, Iaizzo PA: Assessing wound severity using color and infrared imaging of reactive hyperemia. Wound Repair and Regeneration, 4:386-392, 1996.
4. Hansen GL, Sparrow EM, Kokate JY, Leland KJ, Iaizzo PA: Wound status evaluation using color image processing. IEEE Transactions on Medical Imaging, 16:78-86, 1997.
5. Kokate JY, Leland KJ, Sparrow EM, Iaizzo PA: Critical thresholds for pressure ulcer formation in a porcine model. Wounds: A Compendium of Clinical Research and Practice, 9:111-121, 1997.
6. Hansen GL, Sparrow EM, Kalieta AL, Iaizzo PA: Using infrared imaging to assess the severity of pressure ulcers. Wounds: A Compendium of Clinical Research and Practice, 10:43-53, 1998.


Patents Related to this research:
• US5837002: Support apparatus with localized cooling of high-contact-pressure body surface areas. Augustine SD, Iaizzo PA, Sparrow EM, Johnson PS, Arnold RC, Stapf DE: Issued November 17, 1998.
• US6010528: Support apparatus which cradles a body portion for application of localized cooling to high-contact-pressure body surface areas: Augustine SD, Iaizzo PA, Sparrow EM, Johnson PS, Arnold RC; Issued January 4, 2000.
• US6123716: Support apparatus which cradles a body portion for application of localized cooling to high contact-pressure body surface areas. Augustine SD, Iaizzo PA, Sparrow EM, Johnson PS, Arnold RC: Issued September 26, 2000.
• US6224623: Support apparatus which cradles a body portion for application of localized cooling to high contact-pressure body surface areas.. Augustine SD, Iaizzo PA, Sparrow EM, Johnson PS, Arnold RC: Issued May 1, 2001.
• US6497720: Support apparatus with a plurality of thermal zones providing localized cooling. Augustine SD, Iaizzo PA, Sparrow EM, Johnson PS, Arnold RC: Issued December 24, 2002.