Critical Reviews™ in Biomedical Engineering, 38(1):1–20 (2010)

Models for Thermal Damage in Tissues:

Processes and Applications
John A. Pearce, PhD*
Department of Electrical and Computer Engineering, The University of Texas at Austin, Austin, TX

*Address all correspondence to John A. Pearce, Department of Electrical and Computer Engineering, The University of Texas at Austin, 1 University Station,
Austin, TX 78712; Tel.: 512-471-4984; Fax: 512-471-6964; jpearce@mail.utexas.edu.

Abstract: Irreversible thermal alterations in tissue function and structure are used in clinical applications to
achieve diverse goals, from lower-temperature tumor ablation to higher-temperature tissue fusion and surgical cut-
ting. The typical formulation in tumor hyperthermia studies, the thermal iso-effect dose, derives from cell-survival
studies but describes a single process only over a limited range of temperatures and is thus not suitable for multiple
higher-temperature events. Many other thermal damage processes have been described using the Arrhenius kinetic
rate of formation approach, which has the advantage that it is inherently quantitative in nature and can easily be
compared with quantitative markers of injury or histologic section. The vast majority of Arrhenius studies have been
directed toward measurable cellular effects at relatively low temperatures. Some emphasis in this paper has been
placed on what is known of higher-temperature processes to support the theme of this issue. This review compares
and contrasts the two thermal-damage formulations and reviews methods to convert between them.

Key words: ablation, thermal damage, thermal iso-effect dose, cumulative equivalent minutes, Arrhenius models

I. Introduction Diathermy, therapeutic heating at low temperatures

Heat has been used therapeutically for millennia.
Major1 reports that Neolithic skulls unearthed in
France show clear evidence of thermal cauterization.
The Edwin Smith papyrus (ca. 3000 BCE)2 describes
the use of thermal cautery for ulcers and tumors of the
breast. According to Thevenet,3 French physician Guy
de Chaulliac (1300–1370) is one of the first surgeons
to recommend “operating on hernias using golden
thread rather than cauterization.” According to Kelly
and Ward,4 Nagelschmidt applied diathermy in the
treatment of articular and circulatory disease in 1897.
Additionally, they report that Jules de Riviére demon-
strated “white” coagulation (i.e., without sparking and
carbonization) before the French Surgical Congress
in 1907—and that Doyen found temperatures in the
range of 65°C to 70°C for white coagulation. Doyen5
also applied bipolar radiofrequency (RF) current to
superficial tumors after the method of Pozzi.
(between about 40°C and 45°C), is designed to achieve
analgesia, increase cellular metabolism, and stimulate
local perfusion below thermal-damage thresholds.
The increased perfusion facilitates healing processes
by increasing interstitial oxygen partial pressures, tis-
sue nutrients, antibodies, leukocytes, and phagocytes.
Benefits result from the rapid clearing of metabolites
and mechanical damage debris (as from a sprain).6 Cur-
rently, therapeutic heating from a multitude of sources
is frequently used to promote healing in diathermy, to
initiate apoptosis and necrosis in tumor hyperthermia
therapy; to kill tumors and ectopic foci in myocardium
by ablation; to coagulate blood vessels, fuse tissues,
and shrink collagen; and to achieve surgical cutting.
Modeling these processes remains a challenging, but
important, avenue of research; the processes are kinetic
in nature, and models of them provide necessary deeper
understanding than can be obtained from predictions
of temperature alone.

ABBREVIATIONS

CEM, cumulative equivalent minutes; CHO, Chinese hamster ovary; RF, radiofrequency; TID, thermal iso-effect dose.

11040-8401/10/$35.00  © 2010 by Begell House, Inc. 1

2 Pearce
I.A. Thermal Iso-effect Dose Concept
In tumor hyperthermia therapy, the typically applied
assessment of clinical effectiveness is the “thermal iso-
effect dose” (TID), measured in units of cumulative
equivalent minutes (CEM) at 43°C, as described by
Sapareto7 and adapted from the original work reported
in 1978 by Sapareto and Dewey.8 A successful hyper-
thermia treatment is generally held to require a thermal
dose of 60 CEM, calculated from:
(1)
where RCEM ≈ 0.5 for T > 43°C (the breakpoint
temperature) and 0.25 below 43°C; Ti is the constant
temperature (°C) for time ti (min); and N is the number
of epochs in the treatment. The method has been very
widely applied since its introduction.9–11
I.B. Arrhenius Thermal Damage Models.
Arrhenius rate-of-reaction kinetic models describe the
evolution of thermal damage, and the rate of damage
accumulation is temperature dependent. Arrhenius
models derive from standard physical-chemical ther-
modynamics typically used to predict reaction-product
formation. The kinetic nature of thermal-damage devel-
opment is important to understanding observed results.
For example, excessive longer-term heating, even in the
relatively benign mid-40s Celsius, for greater than tens
of minutes can result in edema as the gaps between
endothelial cells widen to allow plasma migration into
the interstitial space.6 Edema is not usually observed as
a thermal-damage mechanism in short-term heating
(tens of seconds or less). Whether thermal damage
will be observed depends on both the temperature
and the time of exposure; the processes are kinetic in
nature, meaning that they are rate-limited. The kinetic
nature of thermal-damage development is often lost
in discussions of “threshold” temperatures but should
not be overlooked.
The first application of Arrhenius rate-of-formation
kinetic models to thermal burns was by Henriques and
Moritz in 1947,12 who formulated the prediction in
terms of a dimensionless damage parameter, Ω:
(2)
where A is the “frequency factor” (s–1), Ea is an energy
barrier ( J mole–1), R is the gas constant (8.3143 J mole–1
K–1), T is temperature (K), and τ is total experiment
time (s). A and Ea characterize the thermal damage
process and must be determined experimentally. An hour
of heating yields very different results from seconds at
the same temperature: temperatures that create thermal
burns during long exposures may be well tolerated for
short times. Consequently, it is not instructive to report
thermal-damage thresholds in terms of temperature
alone; the time of exposure is equally important and
must be included whenever thermal damage is discussed.
Additionally, inspection of the functional nature of
Equation 2 suggests that damage accumulates at all
temperatures above absolute zero. While this is implied
mathematically, in practice, no damage-process model
is valid below the lowest temperature at which the
process results have been observed.
Ultimately, the study of thermal damage reduces
to determining process kinetic parameters (activation
energy and frequency factor). This review describes the
application of the two typically used forms of thermal-
damage models, the TID method and Arrhenius
formulations, in models of particular processes and
applications. These processes have been extensively
studied at moderate temperatures in cell culture, a very
important avenue of research. An elegant and thorough
survey of this work may be found in the comprehensive
analysis by He and Bischof,13 which is filled with many
pertinent and incisive observations of both heating and
cryogenic modalities—one of many exemplary publica-
tions from this group and its alumni. The emphasis in
the current paper is on higher-temperature applications
for ablation, tissue fusion, and surgical cutting, about
which there have been considerably fewer studies and
therefore much less is known.
II. THERMAL ISO-EFFECT DOSE:
Cumulative Equivalent Minutes
TID is derived from studies of the thermal sensitivity
of tumor cell lines in vitro, specifically from a standard
tumor cell line, Chinese hamster ovary (CHO) cells,
but the method turns out to be equally applicable to
other cell lines as well.7 The basis for the measure is
the ability of the cell line to continue to form colonies
as the temperature increases.
Critical Reviews™ in Biomedical Engineering
Models for Thermal Damage in Tissues 3

The thermal sensitivity of CHO cells was deter-

mined in vitro and is depicted in Figure 1. The slope of
the cell-survival curve (Fig. 1A) during the constant-rate
segment (i.e., where the process is first order) deter-
mines the cell-survival-time constant, D0, for the plot
in Figure 1B. Deviation from first-order behavior is
often observed when the cell count is very low, as can
be seen in the longer-duration segments in the figure.
Note that there is a prominent breakpoint (i.e., change
of slope) at 43°C in Figure 1B.

II.A. Foundations of the TID Method

The time constant of cell deactivation at constant
temperature, D0 (min), describes the cell-surviving
fraction, S/N0 , after exposure at constant temperature,
T, for (t – t0) min:

(3)

where N0 viable cells are counted at t0. From survival

curves, the “reaction rate,” k = dΩ/dt, is related to the
parameters of Equation 2 by:

(4)

Figure 1B is a plot of k = 1/D0 vs T–1 (K–1), with T

(°C) superposed (adapted from the original publica-
tion8). There is a prominent change in slope of the
Figure 1B plot (a breakpoint) at 43°C. For tem-
peratures above 43°C, the fit parameters are: ln{A} =
229.0 (i.e., A = 2.84 × 1099 s–1) and Ea = 6.18 × 105 ( J
mole–1), calculated from Equation 4 by least-squares
fit to the data in Figure 1B.
The model parameter, RCEM, signifies the rate at FIGURE 1. (A) Cell survival (colony formation rate) curves
as a function of temperature for asynchronous CHO cells
which the process accumulates. That is, RCEM ≈ 0.5
in culture. (B) Arrhenius plot of inactivation inverse time
means that an exposure of 1 min at 44°C is equivalent constants (1/D0) from Sapareto et al., 19788 for both
to an exposure of 2 min at 43°C. For time-varying asynchronous and G1-phase cells.
temperatures, the CEM43 criterion is calculated from:

(5) II.B. Limitations of the TID Method

and Tbreak is the breakpoint temperature. Different tis-
sues have different thermal sensitivities; for example,
tissues of the central nervous system are known to be
generally more thermally sensitive than those of the
rest of the body.14
Although this measure of thermal dose is in widespread
use in tumor-hyperthermia studies, it suffers from
several limitations. First, although derived from an
Arrhenius model, it constitutes a comparative rather
than predictive parameter: that is, it normalizes time-

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4 Pearce

varying thermal histories so that different treatments

can be compared on a common basis. TID does this
very well, but it does not predict a particular tissue effect
and is therefore not very useful for the wide range of
thermal alterations observed in tissues, especially at that
elevated temperatures required for ablation, tissue fusion,
and surgical cutting (50°C to 150°C). Second, TID
provides no information directly applicable to ablation
studies; collagen, for example, can be exposed to 43°C FIGURE 2. Native-state molecules surmount an energy
for extremely long time intervals without showing any barrier, ΔH* (J mole–1), at overall reaction speed, k (s–1),
sign of thermal alteration. Third, the TID method can- to form denatured protein products.16
not be compared to quantitative means of assessment
such as a damage fraction in histologic section. Fourth, III.A. Foundations of the Arrhenius Method
TID is not in the form of a probabilistic model and
cannot be compared to ensembles of experiments. A The kinetic model of Equation 2 derives originally from
quantitative model that predicts the degree of damage, a uni-molecular reaction formulation typical in physical
or a probabilistic formulation, would be more generally chemistry texts; for example,15 when a concentration of
useful. The former can be directly compared to, for native-state molecules, C, surmount an energy barrier,
example, measured fluorescence intensity or to observed ∆H* ( J mole–1), to become “activated” (in some sense),
which is expressed as C*, and may either relax back
damage concentrations in histologic sections. The latter
to the inactivated original state or progress to, in our
can be compared to the frequency of observation in an
case, a thermally denatured state: ∆H* = Ea - RT ≈
ensemble of experiments in which the degree of dam-
Ea for first-order processes. The specific definition of
age is not measurable, but the frequency of occurrence
“concentration” is left to the particular investigator. ∆H*
is observably temperature dependent.
relates to the energy barrier, not the overall reaction
energy, ∆H ( J mole–1), as illustrated in Figure 2.
III. VOLUME FRACTION Arrhenius
Formulation 1. Physical Chemical Process Parameters
The original skin-burn studies of Henriques and In the uni-molecular description, the reaction speed, k
Moritz12 employed calculations of the non-dimensional (s–1), is the Arrhenius kernel:
parameter Ω (Equation 2), and classified relative burn
severity only in terms of Ω at the skin surface. For (6)
example, Ω = 0.53 was assigned to a "first-degree"
where C is the remaining unaltered concentration, and
burn (i.e., superficial irreversible erythema), Ω = 1.0
∆G* is the Gibbs free energy of activation. ∆G* includes
to a "second-degree" burn (i.e., partial thickness, the activation entropy, ∆S*, and enthalpy, ∆H*: ∆G* =
complete trans-epidermal necrosis), and Ω = 104 to a ∆H* – T ∆S*.
“third-degree” or full-thickness burn (i.e., completely In a few steps one can obtain the correspondences
involving the dermis as well). This calculation can be (for ∆S*/R >> 1):
used much more effectively. By looking at its origins in
reaction-product formation, it is obvious that a quan- (7)
titative and/or probabilistic model can be formulated
and is substantially more useful than the calculation of where N is Avogadro’s number (6.023 × 1023) and hP
Ω alone. It is much too limiting, and unnecessary, to is Planck’s constant (6.63 × 10–34 J s), from which, A
apply only one set of coefficients to describe multiple can be calculated by:
thermodynamically independent kinetic processes acting
in parallel, such as occur in complex tissue structures (8)
at substantially elevated temperatures.

Critical Reviews™ in Biomedical Engineering

Models for Thermal Damage in Tissues
At first glance, it looks as though A should be
treated as temperature dependent; however, T is in K
here, and the temperature varies so little over a typical
thermal-damage experiment temperature range (com-
pared with the activation enthalpy term) as to be of
little importance in the total calculation.
2. Comparative-Process Parameters
Because the physical significance of the process param-
eters is not immediately obvious, we introduce three
additional descriptors. The first of these is the “critical
temperature,” Tcrit, the temperature at which the damage
rate (reaction speed) dΩ/dt = k = 1 (as in Equations 2
and 7); the second is the (time-dependent) “threshold
temperature,” T TH, where Ω = 1 (or a specific reference
value, Ωref ); and the third is the time for the process to
achieve Ω = 1 at a constant temperature of, say, 43°C,
τ43 (only useful at low temperature):
(9a)
(9b)
(9c)
In Equation 9c: 2.629 × 103 = R × 316.2 (K), i.e.
(8.3143)(273.16 + 43°C). With the Arrhenius formula-
tion, it is relatively straightforward to recast the damage
model in quantitative terms:
(10)
where P is either the damage fraction, 1 - C(τ)/C(0)
or the probability of observing tissue damage (%),
depending on how the damage process has been
measured. Consequently, Ω = 1 is well above the
"threshold": the damage process is 63.2% complete at
that point. Also, values of Ω above about 5 (i.e., P =
99.3%) are useless markers for either comparison with
Volume 38, Number 1, 2010
5
histology or a probabilistic prediction because the
damage process is plainly saturated.
III.B. Example Thermal-Damage Processes
Thermal-damage processes that are amenable to quan-
titative or probabilistic analysis generally fall into three
categories: i) quantitatively measurable as the thermal
change develops, such as fluorescence intensity; ii)
quantitatively measurable, but only at the conclusion of
the exposure, such as by enzyme histochemistry or in
histologic section; or iii) not quantitatively measurable
necessarily, but identifiable by frequency of occurrence,
such as the occurrence of pyknotic (shrunken and
shriveled) nuclei.
1. Apoptosis
Apoptosis, or programmed cell death, is a complex
biochemical cascade of protein alterations that even-
tually result in the death of cells in multicellular
organisms—a form of cellular suicide. It is presently
under intense investigation because of its far-reaching
implications in cancer (e.g., tumor necrosis factor and
the like),17 the treatment of disease,18 and the immune
response.19 Although not very well understood at this
point, programmed cell death is one hypothesis for the
effectiveness of tumor-hyperthermia therapy. Markers of
programmed cell death include morphological changes
such as “blebbing” (irregular buds in the cell membrane),
cell shrinkage, nuclear disruption (pyknosis), and chro-
matin condensation, among other changes.20
Apoptosis occurs naturally, for example, in tissue-
differentiation processes during embryonic develop-
ment,21 as an intrinsic response to extrinsic signals such
as heat and radiation,22 and to intrinsic signals such as
viral infection.22 There are several applicable staining
techniques to identify apoptosis.23 Apoptosis is differ-
entiated from necrosis in that necrosis is traumatic cell
death due to acute injury (e.g., membrane disruption
or disruption of mitochondria), not cell death due to
triggering of internal biochemical mechanisms.
Bhowmick et al.24 determined Arrhenius param-
eters for the combination of necrosis and apoptosis
in vitro in tissue sections of human prostate: A =
7.78 × 1022 (s–1), Ea = 1.61 × 105 ( J mole–1), Tcrit =
94.2°C, and τ43 = 5.11 × 103 s (85.3 min). The low
values of A and Ea coupled with the high Tcrit indicate
6 Pearce
a relatively “slow” damage process, one that is more
likely to be observed in long-term heating at lower
temperatures, rather than in short-term, higher-tem-
perature heating. Borrelli et al.25 studied cell death in
BhK cells and reported that A = 2.984 × 1080 (s–1), Ea
= 5.064 × 105 ( J mole–1), Tcrit = 55.5°C, and τ43 = 1.51
× 103 s (25.8 min).
Of course, moderate heating also signals other
cellular responses, complicating the analysis of tumor
responses. Some genes are up-regulated while others are
down-regulated, and other heat-sensitive mechanisms
include the cell cycle and DNA repair.26 Moderate
heating also induces cellular-protective mechanisms.
Cells respond to hyperthermia by expressing heat-shock
proteins, chaperone molecules that assist heat-denatured
proteins in refolding into their native morphology.27-33
Beckham et al.33 studied the role of the heat-shock
protein Hsp70 in murine embryonic fibroblasts in vitro
using bioluminescent imaging, and determined the dif-
ference in thermotolerance between cells with intact
Hsp70 production and those in which Hsp70 produc-
tion was blocked. For Hsp-deficient cells pre-shocked
(i.e., heated again 4 h later), A = 6.9 × 10116 (s–1), Ea
= 7.3 × 105 ( J mole–1), Tcrit = 53.2°C, and τ43 = 5.87 ×
103 s (97.9 min). Hsp70 increases thermotolerance in
similarly reheated cells to A = 3.7 × 10157 (s–1), Ea = 9.8
× 105 ( J mole–1), Tcrit = 51.7°C, and τ43 = 22.1 × 103 s
(368 min). Thus, Hsp70 makes an effective marker of
thermal insult that can be imaged.34–36
2. Fluorescent and Vital Stain Markers
Fluorescent markers have been used for several decades
to indicate thermal processes as they develop. In an
early experiment series, Green and Diller37 measured
increased macromolecular leakage from capillary vessels
in the hamster cheek pouch in vivo using fluorescein
isothiocyanate conjugated dextran. Heating increased
the capillary inter-endothelial cell gaps, resulting in
increased migration of the dye-tagged dextran into
the interstitial space. Aggarwal et al.38 applied digital
image processing techniques to measure the diffusion
rates of the fluorescence-labeled dextran in a dorsal
skin flap preparation. Bhowmick et al.39 measured
the loss of fluorescence in Dunning AT-1 prostate
tumor cells in vitro heated at rates of 2°C and 5°C
per minute to temperatures between 40°C and 70°C.
In an analogous preparation, He and Bischof40 exposed
SN12 human renal carcinoma cells to heating rates up
to 130°C min–1, with varying hold times between 0 and
10 min at hold temperatures between 45°C and 70°C,
followed by a 65°C min–1 cooling sequence. The results
for suspended cells differed significantly from those for
attached cells (Table 1) because of the effects of local
stress, suggesting that cellular attachment thermally
stabilizes the cells.
The dorsal skin flap is a standard construct that
allows continuous close observation of skin vasculature
in vivo without anesthesia (once implanted) in diverse
small animal species.41 The skin is opened, elevated, and
clamped between plates supporting removable windows
and allowed to heal. This fixture has been used success-
fully to study diverse vascular phenomena, including
thermal alterations.23,38,42–44 The thermal breakdown
of red blood cells, hemolysis, another primary skin-
burn response, has also been studied with substantial
success.45
Vital stains are used without fixation to identify
viable cells. There are many such stains; a partial list
includes: trypan blue, vital red, neutral red, Nile blue,
methylene blue, acrydine orange, Bismarck brown, and
Janus green. Janus green B has been used to study mito-
chondria in the cornea46 and elsewhere. Indocyanine
green is another common vital stain (and laser chro-
mophore), but its use in retinal surgery has recently come
under scrutiny due to possible toxic effects.47 Another
interesting supravital stain is nitro blue tetrazolium,
which was used by Acosta and Wendel in 1975,48 by
Feldman et al.49 and Lucchesi et al. in 1976,50 and by
many others since, to study myocardial cell function.
Nitro blue tetrazolium stains normal, metabolically
active tissue a dark purple/brown color.
In a follow-up to their earlier 2000 study,39 Bhow-
mick et al.51 used a clonogenic dye regimen for the
analysis of thermal damage in AT-1 cells: Hoechst 3342
is a fluorescent green stain for all cell nuclei (regardless
of viability), and ethidium homodimer dye-1 stains red
the nuclei that have a compromised plasma membrane.
The total number of cells in an image are identified
by the green fluorescent dye, and the relative number
of killed cells with red nuclei are separately counted,
with the ratio constituting a direct measure of P = [1 –
exp(–Ω)] for Arrhenius analysis. In this AT-1 cell study,
below the 50°C breakpoint, A = 1.66 × 1091 (s–1), Ea =
5.68 × 105 ( J mole–1), Tcrit = 52.1°C, and τ43 = 420 s (7
min); above the 50°C breakpoint, A = 173.5 (s–1), Ea =
Critical Reviews™ in Biomedical Engineering
Models for Thermal Damage in Tissues 7

Table 1. Collected Representative Arrhenius Kinetic Coefficients

Process Parameters
A Ea Tcrit τ43
Process (s–1) (J mol–1) (°C) (s) Notes
Cell Death
Sapareto8 2.84 × 1099 6.18 × 105 51.4 447 CHO cells, T > 43°C
Beckham33 6.9 × 10116 7.3 × 105 53.2 5.87 × 103 Murine w/o Hsp
3.7 × 10157 9.8 × 105 51.7 22.1 × 103 Murine w/ Hsp
Bhowmick24 7.78 × 1022 1.61 × 105 94.2 5.11 × 103 H. Prostate
Bhowmick 51 1.66 × 10 91 5.68 × 10 5 52.1 420 AT-1 Cells < 50°C
173.5 1.97 × 104 186 AT-1 Cells > 50°C
Borrelli25 2.984 × 1080 5.064 × 105 55.5 1.51 × 103 BhK Cells
He40 4.362 × 1043 2.875 × 105 71.0 SN12 cells, suspended
3.153 × 1047 3.149 × 105 73.1 SN12 cells, attached
Erythrocytes
Lepock45 7.6 × 1066 4.55 × 105 82.2 Hemolysis
Skin Burns
Henriques12 3.1 × 1098 6.28 × 105 59.9 Not recommended
Diller 60 8.82 × 10 94 6.03 × 105 58.6 T ≤ 53°C (same data)
1.297 × 1031 2.04 × 105 69.3 T > 53°C
Weaver61 2.19 × 10124 7.82 × 105 55.4 T ≤ 50°C
1.82 × 1051 3.27 × 105 60.1 T > 50°C
Brown62 1.98 × 10106 6.67 × 105 54.6 8.04 × 103 Microvessels
Retinal Damage
Welch134 3.1 × 1099 6.28 × 105 56.6 Whitening
Collagen Changes
Maitland78 1.77 × 1056 3.676 × 105 68.2 Rat tail birefringence
Pearce74 1.61 × 1045 3.06 × 105 80.4 Rat skin birefringence
Aksan102 1.136 × 1086 5.623 × 105 68.1 Rabbit patellar tendon
Miles103 Rat tail tendon, differential scanning
6.658 × 1079 5.21 × 105 67.8
calorimetry
Chen99–101 1.46 × 1066 4.428 × 105 76.4 Shrinkage, rat tail tendon
Muscle
Jacques68 2.94 × 1039 2.596 × 105 70.4 Myocardium whitening
Liver
Jacques135 5.51 × 1041 2.769 × 105 73.4 Whitening, pig liver

1.97 × 104 ( J mole–1), and Tcrit = 186°C—the latter was
a somewhat surprising result relative to other studies
of thermal damage, which nevertheless plots well on
Wright’s line in Figure 3.
The above remain active and important areas
of research, but in this issue we are more interested
in thermal-damage processes and mechanisms that
completely overwhelm all subtle thermal changes
and protective mechanisms and result in substantial
structural and functional alterations to tissue.
3. Skin Burns and Vascular Disruption
Most of the damage mechanisms discussed to this point
have typically been studied in colonies of single-cell
preparations. Tissues and organs are composed of diverse
populations of cells with varying degrees of sensitivity
and are surrounded by supporting structures, which
often makes a difference in their response to thermal
insult. In contrast to single cells, reversible thermal
injury in tissues and organs usually involves some level

Volume 38, Number 1, 2010

8 Pearce
FIGURE 3. Wright’s line126 plot of the Arrhenius coef-
ficients from Table 1 (Equation 23).
of cell death; however, the overall function may not be
impaired significantly.52 Minutes to hours after heating,
edema and hyperemia appear due to the release of vaso-
active agents, increasing the gaps between endothelial
cells, and repair begins a few days later.53 More severe
heating results in irreversible vascular disruption and
consequent progression of tissue death “downstream”
due to ischemia, hypoxia, and other conditions. Novel
methods for assessing skin-burn depth using optical
coherence tomography imaging were described by
Srinivas et al.54 and Pierce et al.55
As mentioned in the introduction, skin burns were
the first kinetic thermal damage mechanism studied in
detail.12,56–58 The kinetic coefficients reported by Hen-
riques and Moritz,12 A = 3.1 × 1098 (s–1), Ea = 6.28 ×
105 ( J mole–1), Tcrit = 59.9°C, and τ43 = 1.81 × 105 s (>
3 × 103 min, 2.09 d), have been widely used since but
actually do not fit their original data set very well and
are not recommended. In 1993, Diller and Klutke59 took
another look at the original data (up to the 50°C point),
and if the datum at 52°C is included, as in the followup
publication,60 one obtains: A = 8.82 × 1094 (s–1), Ea =
6.03 × 105 ( J mole–1), Tcrit = 58.6°C, and τ43 = 4.78 ×
104 s (13.3 h). Above 53°C, an obvious breakpoint,
the Henriques and Moritz data are fit by: A =1.297 ×
1031 (s–1), Ea = 2.04 × 105 ( J mole–1), and Tcrit = 69.3°C
(τ43 = 406 s, but this is irrelevant at these temperatures).
The improved coefficients are relatively close to the val-
ues obtained by Weaver and Stoll in thermal-radiation
skin burns,61 who also observed a breakpoint, but at 50°C
(Table 1). Breakpoints in Arrhenius plots are indications
that a different thermal process has taken over.
The primary mechanism of lower-temperature-
range thermal damage in skin burns is the disruption
of vasculature in the dermis and in the subpapillary and
subdermal vascular plexuses. In a related process, Brown
et al.62 reported coefficients for the disruption of tumor
microvasculature of A = 1.98 × 10106 (s–1), Ea = 6.67 ×
105 ( J mole–1), Tcrit = 54.6°C, and τ43 = 134 min.
4. Ablation
The term “ablation,” from the Latin “ablatus,” the
past participle of “auffere” (to carry away),63 is used
in several different contexts. Surgical ablation means
excision or extirpation. Similarly, in general engineering
terminology, ablation usually implies the creation of a
mass defect, as in ablative heat transfer (aerospace) or
glacial erosion (earth science). In clinical ablation—
cardiac ablation, tumor ablation, endometrial ablation,
and like processes—the goal is frequently to inactivate
the tissue in situ, leaving it in place to form scar tissue
(i.e., to remove it from the inventory of physiologically
active tissue). The US Food and Drug Administration
indexes approximately 11,000 articles related to clinical-
ablation devices,64 a testament to the importance of
these clinical applications.
Collectively, thermal damage from cryogenic, RF,
microwave, ultrasound, or laser sources is applied to
specific sites to achieve ablation. Interstitial applicators
are typically used, and the usual goal is an ablative lesion
larger in dimension than the applicator. He and Bischof13
provide a thorough description of cryogenic ablation.
Here, we look at elevated temperature ranges.
One or more of the previously described moderate-
temperature mechanisms are only likely to be observed
at the edges of the lesion. The essential feature of an
ablation lesion is that cellular protective and repair
mechanisms, such as the heat-shock proteins, are
essentially irrelevant due to the level and rate of heat-
ing applied for the bulk of the lesion volume (although
they may effectively mark the lesion’s outer boundary).
A typical severe acute lesion consists of a hemorrhagic
outer ring due to vascular disruption, a coagulative
heat-fixed “white” necrotic annulus, and often an inner
carbonized disk that may include steam vacuoles or
craters.52,65,66 The following higher-temperature thermal
damage mechanisms may all be at work in the central
Critical Reviews™ in Biomedical Engineering
Models for Thermal Damage in Tissues
region of ablation lesions, while the cellular damage
processes may be observed at their periphery.
5. Birefringence Loss in Muscle and Collagen
Native-state muscle, cardiac, skeletal, and smooth, is
“birefringent,” or able to rotate the polarization of
visible light. This is the source of the histologically
identifiable “A-band” (anisotropic band) in the sarcom-
ere of skeletal and cardiac muscle. Thermally damaged
muscle loses this property due to disruption in the
actin-myosin array, a marker of substantial structural
and functional damage in the sarcomere.67 As a result,
easily identifiable boundaries of thermal damage and
gradation in relative intensity directly comparable to
C(τ)/C(0) can be identified in histologic section through
transmission polarizing microscopy (Fig. 4a). In a
good section, one can measure the relative intensity
of the birefringence signal, which makes a quantitative
thermal damage assay amenable to damage-fraction
calculation. The zone of birefringence loss corresponds
approximately to the grossly observable whitened zone
in an acute myocardial lesions, for which Jacques and
Gaeeni provide an estimate of kinetic parameters
(Table 1).68
Cardiac ablation is used as a palliative treatment
for several types of atrial and ventricular fibrillation
induced by ectopic foci, although it is most practical
for procedures in the atria.69,70 The most common
heating method is by RF current,69 although micro-
wave and ultrasound are also feasible. Certainly, by
the time birefringence is lost in cardiac muscle, it has
been damaged to the point of complete dysfunction.
However, cardiac muscle may be irreversibly damaged
at less-severe heating levels. Cardiac muscle has a sub-
stantial electrical permittivity due to the transmembrane
charge distribution that is substantially reduced when
it collapses.71,72 Changes in permittivity may also prove
to be a useful measure of cardiac ablation success, but
this has not been studied to date.
Collagen is similar in that the regular structure
of its rope-like fibers (Fig. 4b) is also birefringent,
and this birefringence is lost when the collagen is
thermally damaged.52,67,74–77 Arrhenius coefficients for
birefringence loss in collagen may be found in Pearce
et al.74 and Maitland et al.75,78 Collagen damage is
another central feature of skin burns; most animal skin
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9
anatomy is significantly different from that of human
and pig skin.79
6. Collagen Denaturation and Shrinkage
Extensive thermal damage in collagen results in
an amorphous glassified or gelled state, “hyaliniza-
tion.”52,66,76 Achieving a hyalinized, gelled state is
essential in tissue-fusion processes.80-83
Less-severe thermal alteration shrinks collagen
fibers in length by a helix-to-coil transformation.86
The original studies of collagen shrinkage were in the
context of leather tanning processes,87 and have been
intensively studied since. As the fibers shrink in length,
they swell, maintaining an approximately constant
volume in a visco-elastic creep process.88 Targeted col-
lagen shrinkage has many practical clinical applications,
from corneal reshaping83–85,89-91 to cosmetic treatment
for wrinkles.92-98
Chen et al.99–101 have developed a kinetic model
that predicts collagen shrinkage based on a series
of experiments in rat tail tendons. The correlations
normalize all of their data to include the influence
of applied stress during shrinkage, indicated by the
normalized shrinkage time, τ2:
(11)
where α is –ln{A} = –152.35, β = 0.0109 (kPa ), P is
–1
applied stress (kPa), M = Ea/R = 5.3256 × 104 (K);
that is, A = 1.46 × 1066 (s–1) and Ea = 4.428 × 105 ( J
mole–1). The signs are reversed in Equation (11) because
τ2 effectively appears in the denominator of a shrinkage
calculation. In use, the effective τ2 is integrated (i.e.,
∆t/τ2), and at the conclusion of heating the normal-
ized time, ν = ln{t/τ2}, is fit to the data to determine
the shrinkage:
(12)
where ξ is the collagen shrinkage (%), νm = –0.77 ±
0.26, a normalized reference time, a = 2.48 ± 0.438,
a0 = 1.80 ± 2.25, a1 = 0.983 ± 0.937, b0 = 42.4 ± 2.94,
and b1 = 3.17 ± 0.47 (all in %). A predicted shrink-
age in excess of about 60% signifies gelled amorphous
(hyalinized) collagen, so the model can be used for
multiple purposes. After shrinkage (in the absence of
10
gellification) and during cooling, the collagen fibers
relax to slightly longer lengths.86, 99–101
Other models for collagen denaturation include
those applied by Aksan et al.86,102 and Miles et al.103,104
based on coefficients derived from differential scanning
calorimetry, a very powerful experimental method.13
Figure 5 illustrates collagen shrinkage in the cornea.
7. Vaporization and Steam Formation
Evaporation of tissue water from the surface makes
a measurable contribution to the overall surface heat
transfer above approximately 60°C.105 Torres et al. suc-
cessfully applied experimentally derived evaporation
rate correlations,106 Stelling’s formula, to predict the
temperature history of continuous-wave argon laser
irradiation (514 nm) in air on aorta, beef myocardium,
and polyacrylamide gel. Stelling’s formula is:
(13)
where ζ is surface water loss rate (m s ), As = 7.31 ×
–1
10–11 (m Pa–1 s–1), Bs = 1.2 × 10–11 (Pa–1), u is free
stream velocity above the surface (m s–1), Ps is saturation
pressure (Pa) at the surface temperature, T, and at the
environmental temperature and relative humidity, Tenv
and RH, respectively. Stelling’s formula was originally
derived from solar-pond data, but provides a useful and
easily implemented construct for numerical model work.
Surface-water evaporation is even more important to
the calculations when the laser wavelength is primar-
Pearce
FIGURE 4. a) Birefringence loss in rab-
bit cardiac muscle due to argon laser
irradiation; Mallory’s trichrome stain,
original magnification ×40. b) Sketch of
collagen fibril morphology from Pearce
200673 (used with permission).
ily absorbed by tissue water, such as for Tm:YAG (λ
= 2.01 µm), Ho:YAG (2.09 µm), Er:YAG (2.94 µm),
and CO2 (10.6 µm) lasers.
At higher temperatures and heating rates, such as
for surgical cutting, steam formation is almost always
a dominant thermodynamic mechanism; tissue water is
by far the most thermodynamically active constituent
in tissue. Laser and RF electrosurgical cutting processes
depend on rapid steam evolution to separate tissue
layers with minimal radiating thermal damage.4,108–110
The thermodynamics are intricate: at only a few degrees
of superheat (above the saturation boiling temperature
at local pressure), the steam evolution rate increases
extremely rapidly, and there are numerous steam-bubble
nucleation centers in all tissue structures. Consequently,
as a practical matter in relatively “open” tissue structures
(i.e., not highly compartmentalized), one may often
treat the boiling process as essentially isothermal at the
saturation temperature.52 In compartmentalized tissues
such as large arteries, as steam evolves the local pressure
rises: at 100°C, the specific volume of saturated steam is
more than 1.3 × 103 times that of the saturated-liquid
phase.111 Below the surface, evolved steam raises the
local pressure, which in turn raises the boiling-point
temperature.52,112 Figure 6A illustrates such an event, in
which a temperature of 175°C corresponds to a satura-
tion pressure of 10 atmospheres, which is the energy
source that drives the explosion plume.
Including steam evolution in the energy balance
reveals some of the intricacy. The development summa-
Critical Reviews™ in Biomedical Engineering
Models for Thermal Damage in Tissues
FIGURE 5. Application of collagen shrinkage. a) Corneal
collagen heated by a RF needle electrode; original mag-
nification ×25; bar = 0.1 mm, H&E stain. b) Transmission
polarizing microscopy view of the same section; birefrin-
gence loss near needle electrode is evident, as is “straight-
ening” of collagen fibers just outside of the birefringence
loss zone, indicating shrinkage. From Pearce 200184 and
Pearce and Ikei 200785 (used with permission).
rized here is more completely described in the chapters
by Pearce and Thomsen.52,113 Briefly, the left side of
the energy balance (net rate of energy deposition) is
modified to include expansion and phase-change effects
(metabolic and perfusion heat are truly negligible in
these processes):
(14)
where ρ is density (kg m–3), h is specific enthalpy
( J kg–1), P is liquid pressure (Pa), Qgen is the volume
power deposition (W m–3), k is thermal conductivity
(W m–1 K–1), ∂m/∂t is the rate of mass vaporization
of water per unit volume (kg s–1 m–3), and ∆hfg(T) is
the temperature-dependent phase-change enthalpy
Volume 38, Number 1, 2010
11
( J kg–1). This formulation includes phase change in
both the left and right sides; it applies to the liquid-
phase water-tissue composite and can be inserted into
numerical models by employing the following correla-
tions for saturation pressure and density, derived from
steam tables:111
(15)
where ∆hfg is in J kg–1 and T is in °C. The liquid-phase
saturation pressure is fit by (r2 = 1.000):
(16)
where Psat is in kPa (kN m–2) and T is in °C. Similarly,
the liquid-phase density is (r2 = 0.998):
(17)
where ρsat is in kg m–3 and, T is in °C. From these cor-
relations, it is a simple matter to derive temperature-
dependent expressions for ∂P/∂T and ∂ρ/∂T. Ordinarily,
including the expansion term ∂ρ/∂T would not be
important in free surface water, but it is the source of
energy driving a debris plume and so is important in
confined spaces such as cells and tissue structures such
as vessel walls, as shown in Figure 6A. An additional
energy balance similar to Equation 14 is required for
the generated gas phase as well (coupled with a suitable
state equation because of its compressibility); however,
none has been published to date because of a shortage
of suitable biomechanical parameters for the migration
of vapor phase through tissues.
The embedded lesson here is important. Bipolar
electrosurgical sealing of large vessels was not practical
for many years because evolved steam disrupted the
fusion process before reliable fusion of the collagen/
elastin matrix could be achieved (Fig. 6B). The Ligasure®
system (Covidien, Mansfield, MA) employs substan-
tially elevated tissue pressures to raise the equilibrium
boiling point such that vessel fusion temperatures can
readily exceed 100°C, as required for a successful and
repeatable result.114
Recently, Yang et al.115 suggested using a modified
specific heat, C’, on the left side and adding the den-
sity dependence to the perfusion term in the bioheat
equation:
12
FIGURE 6. Boiling processes. (A) Cover illustration
thermogram, argon laser on excised aorta immediately
prior to explosive boiling; each color is 5°C from 80°C to
180°C107; the center temperature in the image is 175°C,
resulting in a saturation pressure of 10 atmospheres.
(B) Cross-section of sealed canine femoral artery by
bipolar RF plate electrodes; Mallory’s trichrome stain,
original magnification ×40; central hole is location of
intra-luminal thermocouple (250 mm diameter); steam
vacuoles (arrows) resulted from low-pressure apposition
of the vessel luminal surfaces.
(18)
where c is the composite specific heat of the tissue ( J
kg–1 K–1), and W includes tissue water density. This
formulation includes the latent heat of vaporization,
but not the changes in tissue density or pressure.
The formulation of Equation 18 is convenient in
that it has the form of the bioheat equation, but it
has to be used with considerable caution. First, “W”
includes much more than the density of water; in fact,
W includes the mass fraction of water in the tissue,
so W = m in Equation 14. Second, applying the rela-
tion directly leads to an aphysical result in the case of
equilibrium vaporization at the saturation temperature,
where dT/dt = 0. In that event, the left side of Equa-
tion 18 is zero for equilibrium boiling at saturation.
Pearce
The right side is certainly not zero—imagine tissue
with zero blood flow at uniform temperature (so that
both the Fourier conduction term and the blood flow
term are zero); Qgen is not zero. The energy-balancing
effect of the mass-loss term (∂m/∂t) on the right side of
Equation 14 has been eliminated, leading to an invalid
conclusion from Equation 18.
The biomechanics of water-vapor diffusion through
tissue have been little studied to date, although Majaron
et al.116 have included some estimates. We lack data for
a complete model, and consequently the relationship
between evolved steam and local pressure elevation is
essentially indeterminate at this point. Steam evolution
is plainly the driving force behind the ejection plumes
that attend pulsed laser110 and similar RF heating appli-
cations. A subsurface steam vacuole is readily observed
in Figure 4a, which was created by a continuous-wave
argon laser (514 nm) at 1.8 W, 3.3-mm beam diameter,
for 2 s in rabbit myocardium.117 Subsurface dissection
due to steam formation is characteristic of high-power
lesions from highly scattered laser sources such as argon
and Nd:YAG lasers. In one such experiment on excised
human aorta in vitro, we measured a surface temperature
of 175°C immediately prior to a steam-driven explo-
sion (Fig. 6A).107 Aorta and other arteries are highly
compartmentalized, in a layered sense, consisting of
multiple elastin and collagen layers interspersed with
smooth muscle.118 The tissue layers create compart-
ments of evolved steam when heated that burst when
the yield stresses are exceeded.
Excimer (excited dimer) lasers, in particular the
ArF laser at 193 nm (UV), have found widespread
use in radial keratotomy procedures.119–124 Ejection
plumes observed in pulsed excimer laser applications
are steam driven as well, even though excimer lasers
are frequently incorrectly described as “cold” lasers.122
In fact, the UV-absorbing bodies (cell organelles such
as the mitochondria) transfer heat rapidly to the cell
water during and for a very short time after the femto-
or nanosecond pulse, thus generating the high pressure
required to drive the plume.
III.C. Determining Arrhenius Coefficients
From End Point Data
The methods for determining Arrhenius coefficients
from differential scanning calorimetry data described
by Miles103,104 and employed to great advantage by
Critical Reviews™ in Biomedical Engineering
Models for Thermal Damage in Tissues
many investigators13,24,40,86,102,125 are powerful. When
the damage marker can be measured as the damage
process develops, one can determine dΩ/dt directly, and
the parameters can be obtained from a straightforward
curve fit to an ensemble of measured slopes, as, for
example, in cell-survival curves.8,39
1. Constant Temperature Experiments
When the heating method is isothermal for a very long
time compared with the warm-up time, the resulting
damage can reasonably be assumed to derive from a
constant-temperature experiment. As long as the dam-
age marker is quantifiable, Arrhenius parameters can
be obtained. That was the method used to determine
A and Ea for birefringence loss in rat skin collagen.81
Given an ensemble of such experiments for which Ω
= 1, one plots the points on Arrhenius axes (ln{τ} vs
1/T) and determines the parameters from the slope
and intercept:
(19)
A constant-temperature experiment for which
Ωi is not 1 can be converted to an equivalent Ω = 1
exposure time, τeq, from:
(20)
That is, τeq = τ/Ωi.
If Ω is not 1 for an experiment ensemble with
known kinetic parameters, but S0 = C(τ)/C(0), the sur-
vival fraction, is known and uniform, then the resulting
AS0 value can be converted to the Ω = 1 (i.e., general)
case, A36.8% by13,125:
(21)
No adjustment in Ea need be made for S0 not equal
to 36.8% because the slope is not affected.13,125
2. Transient Temperature Histories, T(t)
There remains the difficult case of a quantifiable dam-
age marker that can only be measured as an end point
(i.e., not as it develops), Ω(τ), and results from plainly
transient heating histories that cannot be assumed to
be constant temperature. We have developed a method
to estimate Arrhenius parameters in that difficult case,
more completely described in the book chapter.113
Volume 38, Number 1, 2010
13
Briefly, given an ensemble of experiments, a sample
function, transient heating history, Ti(t), is integrated by
Equation 2 using assumed values for A and Ea. A suitable
segment of the ln{A} – Ea plane is scanned (reasonable
estimates can be quickly assembled from Table 1 data,
or from Wright’s line, Equation 23) to find points that
yield the experimentally observed Ωi(τi). The locus of
possible solutions lies along a straight line:
(22)
for which the slope is the temperature and the intercept
the exposure time of an equivalent constant-temperature
experiment, τeq Teq, for which Ω = 1. Note that the
measured Ωi values need not be equal in this method
as long as they are known for each experiment in
the ensemble. The ensemble of equivalent constant-
temperature experiment conditions are then plotted
on standard Arrhenius axes, ln{τeq} vs 1/Teq, to estimate
the parameters for the underlying damage process, as
in Equation 19.
Scanning the ln{A} – Ea plane is not as random a
search process as it might first appear. In 2001, Wright126
observed that all of the published A and Ea pairs plot
very closely to a single line:
(23)
The inspiration for Wright’s plot derives from Miles
and Ghelashvili’s127 use of a “polymer in a box” construct
for the process activation entropy to demonstrate that
∆S* and ∆H* (Equation 7) are proportional. Wright’s
incisive technical brief126 is a necessary reference for
anyone even slightly interested in this area of investiga-
tion; it has to be described as a seminal contribution,
and provides many illuminating insights and so it seems
fitting to label Equation 23 “Wright’s line.” Equation
23 makes an excellent sanity check for any proposed
set of Arrhenius coefficients. A Wright’s line plot of
the Arrhenius coefficients listed in Table 1 has been
included (Fig. 3).
3. Experiment Design Considerations
In view of the extreme sensitivity of the Arrhenius
formulation to the temperature, it is absolutely essential
that all effort be expended to maximally reduce the
uncertainty in T. Experiments in which substantial
14
thermal gradients appear, such as under laser beams,
lead to high uncertainty in the appropriateness and
general usefulness of the model coefficients because
small uncertainties in position lead to large uncertain-
ties in T(t). Badly estimated temperature histories often
manifest in plainly unrealistic predictions of damage
when the timescale of the experiment changes by a
few orders of magnitude. Another hallmark of good
experimental technique is to ensure that several orders
of magnitude in time are included in the experiment
set. An Arrhenius data set comprises holding the short
end of a very long stick indeed, and the uncertainty in
the offset, ln{A}, is enormously enhanced when ln{τ}
covers only a narrow range.
IV. Conversion Between the Two
Methods
A thorough analysis of the relationship between the
TID and Arrhenius methods, and methods for conver-
sion between them, may be found in recent papers by
He et al.125 and Pearce.16 They are briefly summarized
here to conclude the discussion.
RCEM is the ratio of the time (in minutes) required to
achieve an iso-effect dose for a 1°C rise in temperature.
It is related to the Arrhenius coefficients by125:
(24)
This relationship can be quickly derived from two
applications of Equation 2 by setting Ω1 = Ω2, T2 = T1
+ 1 and RCEM = the ratio τ2/τ1. So, for the CHO cell
data (Table 1) at temperatures of 43°C and 44°C, RCEM
= exp{–6.18 × 105/8.337 × 105} = 0.477.
A value for RCEM alone is not sufficient information
to derive Arrhenius coefficients from the TID param-
eter; note that RCEM contains no information about A.
One also requires a value for the time constant, D0,
for at least one convenient temperature, at minimum.
Given RCEM and D0(T), the values for A and Ea can
be calculated, again from two applications of Equa-
tion 2. For example, at 43°C D0(43) ≈ 666 s (Fig. 1b),
and with RCEM = 0.477, a temperature of 50°C would
require:
Pearce
(25)
that is, Tj = 50°C means that tj = 3.7420 s. Applying
Equation 19:
(26)
From which, ln{A} = 232.7 (i.e. A = 1.176 × 10101)
and Ea = 6.29 × 105 ( J mole–1), which is similar to, but
observably different from, the values obtained from
linear regression on Figure 1b data (compare to ln{A}
= 229.0 and Ea = 6.18 × 105). This illustrative calcula-
tion serves to demonstrate the extreme sensitivity of
the results to round-off errors. The sensitivity arises
from the subtraction of large numbers; for example,
–6.5013 = ln{A} – 239.225 and –1.3196 = ln{A} –
234.10 in Equation 26. In the illustrative calculations,
an inordinate number of significant digits have been
used, far in excess of those warranted by the accuracy
of the interpolation of the plotted data in Figure 1b,
to illustrate this limitation.
V. Summary
Thermal alterations in tissues are not phase-change
processes, although they have, very unfortunately, been
described that way.128 Miles et al.104,129,130 were criticized
by Engel and Bachinger131 for making this observa-
tion based on their differential scanning calorimetry
experiments. Miles and Bailey successfully defended
their newly discovered point of view in a subsequent
letter132 pointing out that they also originally thought
collagen denaturation was a phase-change process (as
was the prevailing notion among collagen chemists), but
were convinced by their experiments that it was actually
a rate-limited, irreversible kinetic change. Thermal-
damage processes in general are not phase changes
when they are used to describe major alterations in
tissue structure or function, primarily because they are
just not reversible. I first encountered this simple but
instantly crystallizing observation in a brilliant seminar
presented by Neil Wright in 2000.133 Ice melts and re-
freezes, water boils and condenses: all true phase-change
processes reverse when the temperature changes simply
Critical Reviews™ in Biomedical Engineering
Models for Thermal Damage in Tissues
by absorbing or releasing the phase-change enthalpy by
heat transfer or related means. In contra-distinction, an
egg cannot be “un-fried”; there is no verb for that in our
language for a reason. Resolving the thermal damage
site entails replacing the denatured proteinaceous and
membrane structures with scar tissue, followed by the
healing process, a completely separate and thoroughly
independent thermodynamic event.
Irreversible thermal alterations in tissues are
routinely used in surgery to simultaneously cut and
coagulate tissues, to ablate ectopic foci in myocar-
dium, to ablate tumors by severe heating, and in more
subtle hyperthermia tumor treatments. Surgical cutting
requires rapid boiling of tissue water, an extremely
thermodynamically active tissue constituent, whether
by RF current or laser energy. The fusion of tissues
and sealing of blood vessels depend on gellification of
collagens and elastin plates at high temperature and
high apposition pressure. Collagenous tissues can also
be shrunk to achieve a desired clinical result. Cellular
necrosis and apoptosis may both be observed in tumor
treatment and like applications, and near the edges of
higher-temperature acute lesions.
Using Arrhenius models to predict the probabil-
ity of observation of a discrete (i.e., non-quantitative,
or 0–1) thermal damage process by calculating P, as
introduced earlier, might at first appear to inappropri-
ately stretch the imagination. An “ergodic” stochastic
process is one in which calculation of any statistical
moment with respect to time in one experiment (i.e.,
sample function) gives the same result as calculating
the same statistic across the sample functions at one
fixed time in an ensemble of experiments. Therefore,
if the stochastic nature of the damage process under
study is (at least) ergodic with respect to the mean, then
we can reasonably expect the first statistical moment
to be the same whether computed across an ensemble
of experiments or with time for a single experiment.
Consequently, as mentioned earlier, it may be useful
to apply the Arrhenius model in this way to a damage
process that is not quantifiable in an analog sense, but
is discretely observable (i.e., present or not present) at
temperatures near the threshold, T TH, for the process.
In fact, I was surprised to find that this approach suc-
cessfully modeled an unpublished series of just such
discrete experiments: the Diller and Klutke Arrhenius
coefficients were predictive of the frequency of observa-
tion in a large ensemble. Future investigators may find
Volume 38, Number 1, 2010
15
it a useful way to analyze such an experiment series
near the threshold of the particular damage process
under study.
In surveying the array of process parameters shown
in Table 1, it might be shocking to observe the range of
A values reported: a spread of approximately 10100 can
be seen. Indeed, these are certainly impressive, if not
frightening, numbers that often require some manipula-
tion to be applied; most calculators only accept up to
1099 as a floating-point number, for example. Practically,
A—or, rather, its logarithm, ln{A}, the process activa-
tion entropy—represents the offset for the process; in
concert with Ea, it establishes the temperature at which
the process becomes active. The rate of damage (the
slope) is determined by the activation energy, Ea, and
small differences in Ea can make huge differences in A.
The logarithm is much less sensitive for obvious reasons,
and in numerical model work the numbers are often
too large to be handled in terms of A, so the formula-
tion is routinely set up to be in the form of dΩ/dt =
exp(ln{A} – Ea/RT). Therefore, in view of the functional
relationship involved and the range of temperatures for
the particular processes, the wide range in A is not really
too surprising; it is characteristic of this type of model.
Wright’s cogent observations126 provide an important
additional illuminating perspective.
Despite the temptation to discuss thermal-damage
processes in terms of threshold temperatures alone,
it must always be kept in mind that the underlying
processes are kinetic in nature: the time of exposure
is equally important as the temperature. In fact, if a
“threshold” temperature must be discussed, the kinetic
nature can easily be included, as was described in
Equation 9b:
(9b)
If the CHO cells are used as an illustrative example,
T TH for a 30-min exposure would be 41.1°C, while if
the exposure time were reduced to 1 min, T TH would
be 45.7°C. This is a substantial difference if one is
concerned about either staying just below or ensuring
that one exceeds the damage threshold. Of course, this
particular damage process is only valid for temperatures
above 43°C (the calculation grossly overestimates the
16
damage rate below 43°C), so the result is for illustra-
tive purposes only.
Kinetic descriptions of the propagation of thermal
damage may be easily incorporated into numerical
model predictions to extend the significance of the
model results to observable tissue effects, rather than
being limited to predictions of temperature fields
alone. Multiple processes can be included in parallel
and actually compared with clinical assessments such
as histologic sections or vital stain images. The signifi-
cance and usefulness of the results are thus magnified
many times over. As a consequence, the number of
experiments required to complete a device design or
to establish the efficacy of a method or device may be
reduced. Dosimetry and treatment planning may also
be placed on a more quantitative basis.
Many important thermal-damage processes at
moderate and low temperatures have been quantitatively
studied in cell preparations, but many others remain. A
smaller number of processes have been quantitatively
studied at higher temperatures in intact tissues, a difficult
arena. A key element in higher-temperature thermal-
damage studies is the identification of a quantitative
marker. At this time, we have only a few of them, and
those that we do have appear acutely. It is well known
that thermal damage accumulates post-exposure as tissue
vasculature collapses and cells and tissues that survived
the initial thermal insult die from ischemia, hypoxia,
or a related cause. The post-injury healing response is
another matter entirely, and virtually no quantitative
descriptions are presently available.
Higher-temperature exposures become substantially
more complicated when tissue water boils. A number
of biomechanical parameters are required before more
complete analyses are feasible, analyses that include
mechanical disruption due to induced stresses such as
surgical cutting. Obviously, much more work remains
to be done on higher-temperature measures and models
of thermal damage and repair.
ACKNOWLEDGMENT
Partial support for this work was provided by the T.L.L.
Temple Foundation.
Pearce
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3. Thevenet A. Guy de Chauliac (1300–1370): The “father of
surgery.” Ann Vasc Surg. 1993 Mar;7(2):208–12.
4. Kelly HA, Ward GE. Electrosurgery. Philadelphia: W.B.
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