Abstract
Background: Many studies have shown that nicotine negatively impacts
fracture healing and bone fusion processes. However, very little is known
about its effect on tendon and ligament healing. The goal of the present study
was to evaluate the effect of nicotine on tendon-to-bone healing.
Methods: Supraspinatus tendons in both shoulders of seventy-two rats
were transected and repaired to the humeral head. Osmotic pumps were implanted
subcutaneously, and nicotine or saline solution was delivered for ten,
twenty-eight, or fifty-six days. Cell morphology was evaluated with use of
histologic sections. Cells were counted, and proliferating cell nuclear
antigen (PCNA) immunohistochemistry was performed to assess cellular
proliferation. In situ hybridization was performed to measure type-I collagen
mRNA expression. Biomechanical and geometric properties were assessed.
Results: Inflammation persisted longer in the nicotine group than in
the saline solution group. Cellular proliferation was higher in the saline
solution group than in the nicotine group at the early time-points. Type-I
collagen expression was higher in the saline solution group at twenty-eight
days. Mechanical properties increased over time in both groups. Maximum stress
was significantly lower in the nicotine group than in the saline solution
group at ten days. Maximum force was significantly lower in the nicotine group
than in the saline solution group at twenty-eight days. Maximum force was
significantly higher in the nicotine group than in the saline solution group
at fifty-six days. Stiffness was not different between the groups at any
time-point.
Conclusions: Nicotine caused a delay in tendon-to-bone healing in a
rat rotator cuff animal model. Mechanical properties increased over time in
both groups, but the properties in the nicotine group lagged behind those in
the saline solution group. Chronic inflammation and decreased cell
proliferation may partly explain the inferior biomechanical properties in the
nicotine group as compared with the saline solution group.
Clinical Relevance: Failure of rotator cuff repair is a major
clinical problem. The adverse effect of nicotine on rotator cuff healing noted
in this clinically appropriate animal model may be an important clinical
consideration.
Rotator cuff tears are a common problem, yet short to intermediate-term
recurrence rates after repair have been reported to be as high as
94%1,2.
Factors thought to be associated with the high failure rate include patient
age, tear size, tear chronicity, and muscle
degeneration1,2.
Specific patient-related factors that affect healing, however, have not been
identified. It is well established that smoking has an adverse effect on
health3-6.
Currently, there are more than 50 million smokers in the United
States7. While most
studies have concentrated on the effect of smoking on pulmonary and
cardiovascular health, studies also have demonstrated a detrimental effect on
wound
healing7-11.
Nicotine has been identified as a toxic component in cigarettes and has been
shown to have a negative impact on revascularization and collagen
production8.
While multiple studies have shown that nicotine negatively impacts fracture
healing and bone fusion
processes12-16,
very little is known about its effect on tendon and ligament healing. Studies
have indicated that the mechanism of action of nicotine in bone healing is
vasoconstriction and inhibition of growth-factor
expression17,18.
Whether these mechanisms result in a similar detrimental effect on tendon
healing remains undetermined. Therefore, the purpose of the present study was
to examine the effects of nicotine on rotator cuff injury and repair with use
of an established rodent
model19. Our main
objective was to determine whether nicotine has an effect on the biomechanical
and histological properties of the repair. We hypothesized that nicotine would
delay tendon-to-bone healing, as demonstrated by a decrease in ultimate force
and stiffness at early time-points, and that decreased mechanical properties
would be reflected in histological changes.
Animal Injury Model
All procedures were approved by the Institutional Animal Studies Committee.
Supraspinatus tendons in both shoulders of seventy-two adult male
Sprague-Dawley rats (weight, 350 to 400 g) were transected and repaired to the
humeral head as described
previously19.
Briefly, a skin incision was made over the craniolateral aspect of the
scapulohumeral joint. The deltoid muscle was detached sharply from the
posterior, lateral, and anterior aspects of the acromion and was split
distally. The supraspinatus was detached sharply at its insertion on the
greater tuberosity. A 0.5-mm drill-hole was made transversely in an
anteroposterior orientation through the proximal part of the humerus. Any
fibrocartilage at the insertion was removed by scraping with a scalpel blade.
The tendon was grasped with a double-armed 5-0 proline suture with use of a
technique similar to the Mason-Allen method. The suture was passed through the
drill-hole, and the tendon was reapposed to its anatomic position. It is
important to note that this is an injury model that approximates an acute
rotator cuff injury and not a chronic degenerative rotator cuff tear.
Osmotic pumps (2ML4; Alzet, Cupertino, California) were implanted
subcutaneously, and nicotine (45 mg/mL) or saline solution was delivered at a
rate of 2.5 µL/hr for up to fifty-six days. The rats were randomized to
receive either nicotine or saline solution by means of systematic allocation.
The sequence was frequently reversed, and the surgeon (L.M.G.) was blinded to
the group at the time of surgery. Blood levels of nicotine and cotinine (a
breakdown product of nicotine) were measured every two weeks and demonstrated
the controlled systemic release of nicotine
(Table I). The nicotine levels
in our study were consistent with levels that have been shown to delay
fracture healing and were comparable with those in an adult who smokes twenty
to thirty cigarettes a
day20-22.
The rats were killed at ten, twenty-eight, and fifty-six days, with twelve
rats being killed at each time-point in each group. There were no repair
failures in either group.
Histology-Based Assays
Two specimens were obtained from each group for histological analysis. The
tendon with its attachment to bone was processed with use of standard
techniques. Specimens were fixed overnight in 4% paraformaldehyde and were
decalcified in 14% EDTA. Precautions were taken to maintain mRNA integrity
(e.g., all solutions were treated with 0.1% diethylpyrocarbonate). Specimens
were embedded in paraffin, sectioned at 5 to 7 µm, and dried for one hour
at 60°C. Sections were stained with toluidine blue to examine
fibrocartilage formation and with hematoxylin and eosin to examine cell
morphology. Tissue sections were evaluated blindly by a pathologist (N.H.) for
inflammation, fibrocartilage formation, vascular proliferation, and fibroblast
proliferation.
In Situ Hybridization
A rat cDNA probe for type-I collagen was used to measure mRNA expression. A
1.5-kb EcoRI/EcoRI fragment from clone
HF67723 coding for
pro-a (I) collagen was subcloned into the pBluescript II KS(+) vector
(Stratagene, La Jolla, California). To synthesize an antisense riboprobe for
pro-a (I) collagen, the resulting vector was linearized with Hind III
and transcribed with use of T3 RNA polymerase. The sense riboprobe was
synthesized with use of T7 RNA polymerase, while linearizing with Bam HI.
Specimens for collagen probes were hybridized to gene-specific
33P-labeled sense and antisense riboprobes (2.5 ×
105 cpm/µL) according to the methods of Lyons et
al.24 and as
described
previously19,25,26.
Slides were coated with Ilford K5 emulsion, developed after seven to fourteen
days of exposure, and stained with toluidine blue. Expression was visualized
with use of darkfield microscopy.
Immunohistochemistry for PCNA
Proliferating cell nuclear antigen (PCNA) immunohistochemistry was done in
accordance with the manufacturer's protocol (Zymed Laboratories, San
Francisco, California) as a measure of proliferation. Antibody was visualized
by incubation with diaminobenzidine (DAB) for four minutes. Tissue was
counterstained with Mayer's hematoxylin.
Semiquantitative Evaluation of Protein Levels and mRNA
Expression
Levels of protein and mRNA at the healing insertion site were graded by
three investigators (L.M.G., S.T., and S.Y.R.) who were blinded with regard to
specimen group. Grading was performed with use of printed standards
representing high (4), intermediate (3 and 2), low (1), and undetectable (0)
levels19,25,27.
Cell Density
To measure cellularity, sections were stained with propidium iodine
(Invitrogen/Molecular Probes, Carlsbad, California) to label cell nuclei and
were viewed under fluorescent light. Images of the healing tissue were
captured and thresholded, and cell nuclei were counted with use of Scion Image
(Scion Corporation, Frederick, Maryland). Cell density was then calculated by
dividing the total number of cells by the measured tissue area.
Geometry and Biomechanics
Ten specimens from each group were used for biomechanical testing. The
tendon-humerus unit of each specimen was dissected in a standard fashion. The
overlying deltoid and acromion were removed. The supraspinatus muscle was
removed subperiosteally from the supraspinatus fossa, leaving the
bone-tendon-muscle intact. Specimens were stored in a freezer at 20°C
until testing. Specimens were thawed, and the humerus was embedded in an
aluminum tube with use of polymethylmethacrylate. Testing was performed with
the shoulder at 90° of abduction in a materials testing machine (model
8841; Instron, Norwood, Massachusetts). The humerus was clamped with its long
axis in the horizontal plane. The proximal end, at the origin of the
supraspinatus tendon, was glued between two pieces of sandpaper. The
sandpaper-tendon was clamped vertically in a soft-tissue clamp. Stress was
calculated as the tensile force divided by the cross-sectional area. Specimens
were subjected to a preload of 0.2 N and were preconditioned for five cycles
to 0.38 mm of displacement (approximately 5% of gauge length at a rate of 0.1
mm/s). A stress relaxation test was then performed for 300 seconds at 0.38 mm
of displacement followed by 300 seconds of recovery. Specimens were then
tested to failure in tension at a rate of 0.1 mm/s. Ultimate stress, ultimate
force, and stiffness were determined for each specimen. For geometry
calculations, cross-sectional area was calculated at the distal aspect of the
tendon (i.e., at the insertion site). Tendon thickness was quantified with use
of a laser displacement sensor (LK-081; Keyence, Woodcliff Lake, New Jersey).
Tendon width was measured with use of optical methods. The cross-sectional
area was then calculated by assuming an elliptical geometry. These methods
provided a fully noncontact procedure for the measurement of cross-sectional
area.
Statistical Methods
Biomechanical and geometric results were compared with use of a two-factor
analysis of variance for group (saline solution or nicotine) and time (ten,
twenty-eight, or fifty-six days) followed by a post hoc pairwise comparison
with use of the Fischer least-squares-differences test. The level of
significance was set at p < 0.05. Histology-based results (e.g., cell
morphology, mRNA expression, cellular proliferation, and cell density) are
semiquantitative in nature, with only two specimens per group, and were not
statistically compared.
Histology
At ten days, the interface between tendon and bone displayed focal damage,
with scattered acute inflammatory cells mixed with a predominant mononuclear
infiltrate in both groups. In both groups, vascular and fibroblast
proliferation was at its highest level at this stage as compared with the
other time-points. At twenty-eight days, the interface displayed focal damage
in both groups. The inflammatory infiltrate was slightly less in the saline
solution group than in the nicotine group. Vascular and fibroblast
proliferation was higher in the saline solution group than in the nicotine
group. At fifty-six days, the interface displayed normal to slight focal
damage in both groups. Acute inflammation was absent in the saline solution
group but persisted in the nicotine group. Vascular and fibroblast
proliferation was similar in both groups.
Cell Density and Cellular Proliferation
Cell density was decreased by 13%, 8%, and 1% in the nicotine group as
compared with the saline solution group at ten, twenty-eight, and fifty-six
days, respectively. Cellular proliferation (i.e., PCNA grade) was higher in
the saline solution group than in the nicotine group at ten and twenty-eight
days (Fig. 1). Proliferation
was similar in both groups at fifty-six days. Cell density and cell
proliferation decreased over time in both groups.
mRNA Expression for Type-I Collagen
Type-I collagen expression was higher in the saline solution group than in
the nicotine group at twenty-eight days
(Fig. 2). Type-I collagen
expression was highest at the earliest time-point and decreased over time.
Geometry and Biomechanics
Geometric and biomechanical results are summarized in
Figure 3 and
Table II. Maximum stress was
significantly lower in the nicotine group than in the saline solution group at
ten days (p < 0.05) (Fig. 3,
Table II). Maximum stress
significantly increased over time in both groups. Maximum force was
significantly lower in the nicotine group than in the saline solution group at
twenty-eight days (p 0.05) (Fig.
3, Table II).
Maximum force was significantly higher in the nicotine group than in the
saline solution group at fifty-six days (p 0.05). There was a significant
increase in maximum force over time. Stiffness was not significantly different
in the nicotine group as compared with the saline solution group at any
time-point (Fig. 3,
Table II). There was a
significant increase in stiffness over time (p < 0.05).
To our knowledge, this is the first study to evaluate the effects of
nicotine on rotator cuff repair. Smoking has a known detrimental effect on the
healing of
bone12-16
and
skin7-11.
It also has been associated with intervertebral disc disease and low-back
pain28-36.
Its effect on tendon healing remains unknown. The decreases in maximum stress
and maximum force that we observed suggest inferior healing and decreased
remodeling due to nicotine. This inhibition of the natural healing process has
potential clinical implications as tendon injuries are among the most common
orthopaedic injuries, both during recreational activities and in the
workplace37. The
present study is most relevant to rotator cuff repair, a frequently performed
procedure37.
The delay in tendon-to-bone healing associated with the administration of
nicotine in this rat rotator cuff model is consistent with what has been
demonstrated in studies of fracture
healing38. Raikin
et al. demonstrated a lag in the formation of cortical continuity in a rabbit
tibial osteotomy model when the animals were exposed to
nicotine38. There
also was a 13% higher rate of nonunion in the nicotine group. Hollinger et al.
demonstrated a negative impact on the healing of parietal bone defects in rats
that had been exposed to
nicotine39. Other
studies have shown that nicotine delays and may prevent spinal
fusion12-14.
Silcox et al. reported that fusion did not occur in the lumbar spines of
rabbits that had received a continuous infusion of
nicotine12. Brown
et al. reported a significantly higher rate of pseudarthrosis after lumbar
fusions in humans with a heavy smoking
history16. Delayed
healing due to smoking also has been demonstrated after soft-tissue
injury7-11.
In the study by Jorgensen et al., a quantitative analysis of collagen
production demonstrated that the production of subcutaneous collagen in
smokers was
impeded8.
In the present study, maximum stress, maximum force, and stiffness
increased over time in both groups, but the mechanical properties in the
nicotine group lagged behind those in the saline solution group at ten and
twenty-eight days. The maximum stress (a material property) in the nicotine
group was significantly inferior to that in the saline solution group at the
early time-points. The inferior material properties are an indication of less
mature scar and less scar remodeling in the nicotine group. Thus, nicotine may
have a negative effect on extracellular matrix degradation. Additionally, it
may have no effect on extracellular matrix production or it may promote the
production of a lower-quality matrix (e.g., type-III collagen rather than
type-I collagen).
Cell density and cellular proliferation were higher in the saline solution
group than in the nicotine group at ten and twenty-eight days, and they were
similar in both groups at fifty-six days. Differences in type-I collagen
expression were evident only at twenty-eight days. At ten days, maximum stress
was significantly higher in the saline solution group whereas maximum load was
not significantly different between the groups. At twenty-eight days, maximum
load was significantly higher in the saline solution group whereas
maximum stress was not significantly different between the groups.
This finding indicates that the structural properties that were tested were
dominated by the suture repair early on. As time progressed and the properties
of the healing tissue began to contribute to strength at the repair site, the
delay in matrix remodeling in the nicotine group became evident.
Unexpectedly, the maximum load was significantly higher in the nicotine
group than in the saline solution group at fifty-six days. This difference
could be explained by increases in collagen crosslinking caused by advanced
glycation end products. These end products are formed by the reaction of
sugars with lysine and arginine residues in
proteins40. Their
accumulation leads to the formation of irreversible crosslinks, resulting in a
more brittle collagen
network41.
Accumulation of proteins by non-enzymatic glycation is one of the underlying
factors associated with diabetes complications, age-related arthritis,
cardiomyopathy, and other protein-deposition
disorders42-44.
Smoking also has been associated with increased advanced glycation end product
formation in gingival fibroblasts, plasma proteins, and
myocardium44-46.
These changes are thought to cause increased susceptibility to injury in
affected tissues. This may explain the difference in maximum force that was
seen in our study, especially given the fact that this difference was seen
only at the later time-point (i.e., only after these end products had
accumulated in the matrix). This change is likely detrimental, as it may lead
to increased susceptibility to injury or failure as the result of a more
brittle matrix and decreased viscoelasticity.
Our histology-based assays could not entirely explain the geometric and
biomechanical changes that were observed. Chronic inflammation and decreased
cell proliferation may partly explain the inferior biomechanical properties in
the nicotine group. The delayed healing also was evident in the decreased
expression of type-I collagen. However, these histological differences between
the nicotine and saline solution groups were small and could only partly
explain the large differences in terms of geometric and biomechanical
properties.
A strength of our study is the use of an established rodent model for
rotator cuff
repair19. The use
of this model makes our findings particularly relevant to rotator cuff injury
and repair. Our use of an osmotic delivery pump is also well established in
the literature for studying the effects of
nicotine12,18,47,48.
We performed consistent monitoring of nicotine and cotinine levels in order to
ensure adequate delivery throughout the time-period studied. A limitation of
our study is that the animal model used is that of an acute injury and repair.
The more common clinical injury to the rotator cuff involves chronic
degeneration followed by tendon tears. However, an acute repair would likely
heal better than a chronic tear, so the effects of nicotine demonstrated in
the present study may be less than those seen in association with the repair
of a chronic tear. Finally, rats may metabolize nicotine faster than humans
do. In the present study, we were careful to maintain levels at those
consistent with an adult smoking twenty to thirty cigarettes per day.
By fifty-six days, there were few differences between the nicotine and
saline solution groups. This finding suggests that there may be a vulnerable
time-period in tendon-healing during which early failure secondary to the
effects of nicotine may be more of a problem. This is important clinically
because often it is during this time-period that repairs are exposed to early
rehabilitation protocols.
Whether or not the effects of smoking are reversible is unknown. We are not
aware of any conclusive studies that have generated definitive guidelines
about perioperative cessation of smoking. Therefore, it is still not known
whether requiring patients to stop smoking prior to surgery will improve or
change the biologic outcome.
Failure of rotator cuff repair is a major clinical problem. Treatment may
require additional procedures, and there are often no reliable or predictable
surgical options. On the basis of the findings of the present study, we
conclude that nicotine causes a delay in tendon-to-bone healing and also
causes a delay in scar degradation and remodeling. Therefore, it is advisable
that patients cease smoking or using tobacco products before undergoing a
rotator cuff repair. Our results also may affect the advisability of using
nicotine patches during the perioperative period. Additional studies are
necessary in order to elucidate the changes in geometry and biomechanics
reported here and to provide potential targets for therapeutic intervention.
?
Harryman DT 2nd, Mack LA, Wang KY,
Jackins SE, Richardson ML, Matsen FA 3rd. Repairs of the rotator cuff.
Correlation of functional results with integrity of the cuff. J Bone
Joint Surg Am. 1991;73:
982-9.73982
1991
[PubMed]
Galatz LM, Ball CM, Teefey SA, Middleton
WD, Yamaguchi K. The outcome and repair integrity of completely
arthroscopically repaired large and massive rotator cuff tears. J Bone
Joint Surg Am. 2004;86:
219-24.86219
2004
Skurnik Y, Shoenfeld Y. Health effects
of cigarette smoking. Clin Dermatol.
1998;16:
545-56.16545
1998
[PubMed][CrossRef]
Routh HB, Bhowmik KR, Parish JL, Parish
LC. Historical aspects of tobacco use and smoking. Clin
Dermatol. 1998;16:
539-44.16539
1998
[CrossRef]
Newby DE, Wright RA, Labinjoh C, Ludlam
CA, Fox KA, Boon NA, Webb DJ. Endothelial dysfunction, impaired endogenous
fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and
myocardial infarction. Circulation.
1999;99:
1411-5.991411
1999
[PubMed]
Kwiatkowski TC, Hanley EN Jr, Ramp WK.
Cigarette smoking and its orthopedic consequences. Am J Orthop.
1996;25:
590-7.25590
1996
[PubMed]
Sherwin MA, Gastwirth CM. Detrimental
effects of cigarette smoking on lower extremity wound healing. J Foot
Surg. 1990;29:
84-7.2984
1990
Jorgensen LN, Kallehave F, Christensen
E, Siana JE, Gottrup F. Less collagen production in smokers.
Surgery. 1998;123:
450-5.123450
1998
[PubMed][CrossRef]
Mosely LH, Finseth F. Cigarette smoking:
impairment of digital blood flow and wound healing in the hand.
Hand. 1977;9:
97-101.997
1977
[PubMed][CrossRef]
Jensen JA, Goodson WH, Hopf HW, Hunt TK.
Cigarette smoking decreases tissue oxygen. Arch Surg.
1991;126:
1131-4.1261131
1991
[PubMed]
Leow YH, Maibach HI. Cigarette smoking,
cutaneous vasculature, and tissue oxygen. Clin Dermatol.
1998;16:
579-84.16579
1998
[PubMed][CrossRef]
Silcox DH 3rd, Daftari T, Boden SD,
Schimandle JH, Hutton WC, Whitesides TE Jr. The effect of nicotine on spinal
fusion. Spine. 1995;20:
1549-53.201549
1995
[PubMed][CrossRef]
Wing KJ, Fisher CG, O'Connell JX, Wing
PC. Stopping nicotine exposure before surgery. The effect on spinal fusion in
a rabbit model. Spine.
2000;25:
30-4.2530
2000
[PubMed][CrossRef]
Glassman SD, Anagnost SC, Parker A,
Burke D, Johnson JR, Dimar JR. The effect of cigarette smoking and smoking
cessation on spinal fusion. Spine.
2000;25:
2608-15.252608
2000
[PubMed][CrossRef]
Cobb TK, Gabrielsen TA, Campbell DC 2nd,
Wallrichs SL, Ilstrup DM. Cigarette smoking and nonunion after ankle
arthrodesis. Foot Ankle Int.
1994;15:
64-7.1564
1994
[PubMed]
Brown CW, Orme TJ, Richardson HD. The
rate of pseudarthrosis (surgical nonunion) in patients who are smokers and
patients who are nonsmokers: a comparison study. Spine.
1986;11:
942-3.11942
1986
[PubMed][CrossRef]
Campanile G, Hautmann G, Lotti T.
Cigarette smoking, wound healing, and face-lift. Clin Dermatol.
1998;16:
575-8.16575
1998
[PubMed][CrossRef]
Theiss SM, Boden SD, Hair G, Titus L,
Morone MA, Ugbo J. The effect of nicotine on gene expression during spine
fusion. Spine. 2000;25:
2588-94.252588
2000
[PubMed][CrossRef]
Thomopoulos S, Hattersley G, Rosen V,
Mertens M, Galatz L, Williams GR, Soslowsky LJ. The localized expression of
extracellular matrix components in healing tendon insertion sites: an in situ
hybridization study. J Orthop Res.
2002;20:
454-63.20454
2002
[PubMed][CrossRef]
Benowitz NL. Clinical pharmacology of
nicotine. Annu Rev Med.
1986;37:
21-32.3721
1986
[PubMed][CrossRef]
Benowitz NL, Jacob P 3rd. Daily intake
of nicotine during cigarette smoking. Clin Pharmacol Ther.
1984;35:
499-504.35499
1984
[PubMed][CrossRef]
Isaac PF, Rand MJ. Blood levels of
nicotine and physiological effects after inhalation of tobacco smoke.
Eur J Pharmacol. 1969;8:
269-83.8269
1969
[PubMed][CrossRef]
Chu ML, Myers JC, Bernard MP, Ding JF,
Ramirez F. Cloning and characterization of five overlapping cDNAs specific for
the human pro alpha 1(I) collagen chain. Nucleic Acids Res.
1982;10:
5925-34.105925
1982
[PubMed][CrossRef]
Lyons KM, Pelton RW, Hogan BL.
Organogenesis and pattern formation in the mouse: RNA distribution patterns
suggest a role for bone morphogenetic protein-2A (BMP-2A).
Development. 1990;109:
833-44.109833
1990
[PubMed]
Thomopoulos S, Williams GR, Gimbel JA,
Favata M, Soslowsky LJ. Variation of biomechanical, structural, and
compositional properties along the tendon to bone insertion site. J
Orthop Res. 2003;21:
413-9.21413
2003
[CrossRef]
Thomopoulos S, Williams GR, Soslowsky
LJ. Tendon to bone healing: differences in biomechanical, structural, and
compositional properties due to a range of activity levels. J Biomech
Eng. 2003;125:
106-13.125106
2003
[CrossRef]
Carpenter JE, Flanagan CL, Thomopoulos
S, Yian EH, Soslowsky LJ. The effects of overuse combined with intrinsic or
extrinsic alterations in an animal model of rotator cuff tendinosis. Am
J Sports Med. 1998;26:
801-7.26801
1998
Heliovaara M, Sievers K, Impivaara O,
Maatela J, Knekt P, Makela M, Aromaa A. Descriptive epidemiology and public
health aspects of low back pain. Ann Med.
1989;21:
327-33.21327
1989
[PubMed][CrossRef]
Frank JW, Brooker AS, DeMaio SE, Kerr
MS, Maetzel A, Shannon HS, Sullivan TJ, Norman RW, Wells RP. Disability
resulting from occupational low back pain. Part II: What do we know about
secondary prevention? A review of the scientific evidence on prevention after
disability begins. Spine.
1996;21:
2918-29.212918
1996
[PubMed][CrossRef]
Cox JM, Trier KK. Exercise and smoking
habits in patients with and without low back and leg pain. J
Manipulative Physiol Ther.
1987;10:
239-45.10239
1987
Deyo RA, Bass JE. Lifestyle and low-back
pain. The influence of smoking and obesity. Spine.
1989;14:
501-6.14501
1989
[PubMed][CrossRef]
Jamison RN, Stetson BA, Parris WC. The
relationship between cigarette smoking and chronic low back pain.
Addict Behav. 1991;16:
103-10.16103
1991
[PubMed][CrossRef]
Boshuizen HC, Verbeek JH, Broersen JP,
Weel AN. Do smokers get more back pain? Spine.
1993;18:
35-40.1835
1993
[PubMed][CrossRef]
Ernst E. Smoking, a cause of back
trouble? Br J Rheumatol.
1993;32:
239-42.32239
1993
[PubMed][CrossRef]
Leboeuf-Yde C, Yashin A. Smoking and low
back pain: is the association real? J Manipulative Physiol
Ther. 1995;18:
457-63.18457
1995
Leboeuf-Yde C, Yashin A, Lauritzen T.
Does smoking cause low back pain? Results from a population-based study.
J Manipulative Physiol Ther.
1996;19:
99-108.1999
1996
[PubMed]
Praemer A, Furner S, Rice DP.
Musculoskeletal conditions in the United States. 1st ed. Park
Ridge, IL: American Academy of Orthopaedic Surgeons;
1992.
1992
Raikin SM, Landsman JC, Alexander VA,
Froimson MI, Plaxton NA. Effect of nicotine on the rate and strength of long
bone fracture healing. Clin Orthop Relat Res.
1998;353:
231-7.353231
1998
[PubMed][CrossRef]
Hollinger JO, Schmitt JM, Hwang K,
Soleymani P, Buck D. Impact of nicotine on bone healing. J Biomed Mater
Res. 1999;45:
294-301. Erratum in: J Biomed Mater Res.
1999;46:438-9.45294
1999
[CrossRef]
Verzijl N, DeGroot J, Oldehinkel E, Bank
RA, Thorpe SR, Baynes JW, Bayliss MT, Bijlsma JW, Lafeber FP, TeKoppele JM.
Age-related accumulation of Maillard reaction products in human articular
cartilage collagen. Biochem J.
2000;350:
381-7.350381
2000
[PubMed][CrossRef]
Verzijl N, DeGroot J, Ben ZC,
Brau-Benjamin O, Maroudas A, Bank RA, Mizrahi J, Schalkwijk CG, Thorpe SR,
Baynes JW, Bijlsma JW, Lafeber FP, TeKoppele JM. Crosslinking by advanced
glycation end products increases the stiffness of the collagen network in
human articular cartilage: a possible mechanism through which age is a risk
factor for osteoarthritis. Arthritis Rheum.
2002;46:
114-23.46114
2002
[PubMed][CrossRef]
Bank RA, Bayliss MT, Lafeber FP,
Maroudas A, TeKoppele JM. Ageing and zonal variation in post-translational
modification of collagen in normal human articular cartilage. The age-related
increase in non-enzymatic glycation affects biomechanical properties of
cartilage. Biochem J.
1998;330:
345-51.330345
1998
[PubMed]
Sady C, Khosrof S, Nagaraj R. Advanced
Maillard reaction and crosslinking of corneal collagen in diabetes.
Biochem Biophys Res Commun.
1995;214:
793-7.214793
1995
[PubMed][CrossRef]
Rajiyah G, Agarwal R, Avendano G, Lyons
M, Soni B, Regan TJ. Influence of nicotine on myocardial stiffness and
fibrosis during chronic ethanol use. Alcohol Clin Exp Res.
1996;20:
985-9.20985
1996
[PubMed][CrossRef]
Katz J, Caudle RM, Bhattacharyya I,
Stewart CM, Cohen DM. Receptor for advanced glycation end product (RAGE)
upregulation in human gingival fibroblasts incubated with nornicotine.
J Periodontol. 2005;76:
1171-4.761171
2005
[PubMed][CrossRef]
Dickerson TJ, Janda KD. A previously
undescribed chemical link between smoking and metabolic disease. Proc
Natl Acad Sci USA. 2002;99:
15084-8.9915084
2002
[CrossRef]
Clark A, Lindgren S, Brooks SP, Watson
WP, Little HJ. Chronic infusion of nicotine can increase operant
self-administration of alcohol. Neuropharmacology.
2001;41:
108-17.41108
2001
[PubMed][CrossRef]
Iwaniec UT, Fung YK, Akhter MP, Haven
MC, Nespor S, Haynatzki GR, Cullen DM. Effects of nicotine on bone mass,
turnover, and strength in adult female rats. Calcif Tissue Int.
2001;68:
358-64.68358
2001
[PubMed][CrossRef]