The Molecular Anatomy of Oral Wound Healing
| Status: | Completed |
|---|---|
| Conditions: | Hospital, Gastrointestinal |
| Therapuetic Areas: | Gastroenterology, Other |
| Healthy: | No |
| Age Range: | 18 - 40 |
| Updated: | 3/3/2019 |
| Start Date: | February 2, 2010 |
| End Date: | February 19, 2019 |
Background:
- Two important properties distinguish the healing process of skin wounds from that of
wounds of the mucous membranes of the mouth (oral mucosa). Although the skin and the
oral mucosa tissues are similar in nature, oral mucosa have more rapid healing and a
lack of scar tissue formation. However, oral wound healing in general has been poorly
studied, and more information is needed to determine how specific aspects of the oral
environment affect the healing process.
- Researchers are interested in identifying various factors that contribute to oral wound
healing. Studying this process would help researchers explore procedures to accelerate
the healing of critically-sized oral lesions formed by trauma, surgery, radiation
therapy, infection, and other damage to the mouth. In addition, research into scar-free
healing could be applied to other mucosal sites to promote healing and minimize
unsightly scars that may compromise the tissue.
Objectives:
- To identify the specific factors that enable rapid and nearly scar-free healing of oral
mucosa.
Eligibility:
- Healthy male volunteers between 18 and 40 years of age.
- Regular cigarette, cigar, and pipe smokers; occasional smokers who smoke more than 1 day
a week or have smoked in the prior month; users of chewing tobacco or betel nut; and
heavy drinkers (three or more alcoholic drinks per day) will be excluded.
Design:
- Participants will have a medical history and examination, and will provide blood samples
at the start of the study.
- Participants will provide oral mucosa samples from the inside of the cheek, taken using
a dermal punch. At the same time, participants will provide skin biopsy samples of
approximately the same size. After the skin and oral mucosa samples are taken,
participants will be divided into three groups for follow-up procedures.
- Group 1: No further samples will be collected. This group will help document the normal
healing process.
- Group 2: A second, slightly larger biopsy, which will include the area of the first
biopsy, will be taken on day 3. Both skin and oral mucosa biopsies will be taken.
- Group 3: A second, slightly larger biopsy will be taken on day 6, in a similar way as
described for Group 2. Both skin and oral mucosa biopsies will be taken.
- Wounds will be photographed with a digital camera on days 3, 6, 9, 13, and 15; and the
healing will be monitored at the scheduled clinic visits.
- Two important properties distinguish the healing process of skin wounds from that of
wounds of the mucous membranes of the mouth (oral mucosa). Although the skin and the
oral mucosa tissues are similar in nature, oral mucosa have more rapid healing and a
lack of scar tissue formation. However, oral wound healing in general has been poorly
studied, and more information is needed to determine how specific aspects of the oral
environment affect the healing process.
- Researchers are interested in identifying various factors that contribute to oral wound
healing. Studying this process would help researchers explore procedures to accelerate
the healing of critically-sized oral lesions formed by trauma, surgery, radiation
therapy, infection, and other damage to the mouth. In addition, research into scar-free
healing could be applied to other mucosal sites to promote healing and minimize
unsightly scars that may compromise the tissue.
Objectives:
- To identify the specific factors that enable rapid and nearly scar-free healing of oral
mucosa.
Eligibility:
- Healthy male volunteers between 18 and 40 years of age.
- Regular cigarette, cigar, and pipe smokers; occasional smokers who smoke more than 1 day
a week or have smoked in the prior month; users of chewing tobacco or betel nut; and
heavy drinkers (three or more alcoholic drinks per day) will be excluded.
Design:
- Participants will have a medical history and examination, and will provide blood samples
at the start of the study.
- Participants will provide oral mucosa samples from the inside of the cheek, taken using
a dermal punch. At the same time, participants will provide skin biopsy samples of
approximately the same size. After the skin and oral mucosa samples are taken,
participants will be divided into three groups for follow-up procedures.
- Group 1: No further samples will be collected. This group will help document the normal
healing process.
- Group 2: A second, slightly larger biopsy, which will include the area of the first
biopsy, will be taken on day 3. Both skin and oral mucosa biopsies will be taken.
- Group 3: A second, slightly larger biopsy will be taken on day 6, in a similar way as
described for Group 2. Both skin and oral mucosa biopsies will be taken.
- Wounds will be photographed with a digital camera on days 3, 6, 9, 13, and 15; and the
healing will be monitored at the scheduled clinic visits.
BACKGROUND:
Two important properties distinguish the process of healing of oral mucosa wounds from those
of the skin: more rapid healing and the absence of scar tissue formation. This is remarkable
given the apparent similarities of the two tissues. There are, however, prominent differences
in the healing environment, such as hydration, growth factor availability, inflammatory
response, and microbial exposure. Knowledge as to the causal contribution of each of these
factors to the differential healing response of the two epithelia is mostly anecdotal, and
oral wound healing has generally been poorly studied. This study seeks to provide a global
molecular definition of oral wound healing in comparison to that of the skin. The overall aim
will be to identify the specific factors that enable rapid and nearly scar-free healing of
oral mucosa. Identification of these physiological and molecular determinants will have
widespread implications for human oral health. Among others, it would provide venues for the
targeted exploration of procedures to accelerate the healing of critically-sized oral lesions
formed by trauma, surgery, radiation therapy, infection, and other oral pathologies, which,
if untreated, lead to permanent disability and dysfunction. Moreover, pathways and/or
molecules identified in these studies which may facilitate rapid, scar-less healing could be
considered for application to non-oral mucosal sites to promote healing and minimize
unsightly scars, which may also compromise the functional integrity of the tissue.
Hypotheses:
- There are significant differences in gene and protein expression between wound healing
in skin and oral mucosa.
- The recruitment of inflammatory cells associated with a large up-regulation of
inflammation-associated genes, including cytokines and chemokines, in the epithelial
cells of skin wounds may account for these differences.
- There are specific gene programs that can explain the presence of significant scarring
in skin tissues but not in oral mucosa.
OBJECTIVES:
The overall objective of this pilot study proposal is to establish the gene and protein
expression profiles during the early stages (1-6 days) of normal oral wound repair. By
comparing these profiles with those of cutaneous wound healing, we may be able to identify
molecules exclusive to oral wound repair that could represent biomarkers of the healing
process or serve as new therapeutic targets in pathological wound healing and cancer. One
specific hypothesis to be tested is that the level of expression of pro-inflammatory gene
networks by wound-infiltrating keratinocytes constitutes the most significant difference
between the human oral and cutaneous wound transcriptomes. The specific hypothesis has been
developed from data obtained from our recent complementary oral and skin wound healing
studies in animals.
ELIGIBILITY:
Healthy male volunteers age 18 to 40 will be enrolled in this study.
DESIGN:
Oral mucosa samples: A sterile 3-mm dermal punch will be used to create uniform,
full-thickness biopsy in the mucosa of the cheek just above the occlusal plane. Circular
pieces of tissue of approximately 2 mm in depth will be removed on the day of biopsy (day 1).
These subjects will be subsequently be randomly grouped as follows:
Group 1: no further samples will be collected; pictures will be taken on days 3, 6, 9, 13,
and 15 (see Timetable). This group will help document the normal healing process under the
conditions of the present study, including the lack of scaring in the area selected for the
initial wound in the oral mucosa as compared with the skin.
Group 2: a second biopsy will be taken on day 3, which will include the area of the first
biopsy with sterile 5 mm punch, following the same procedure as described for day 0; pictures
will be taken according to the schedule set in the Timetable. This second biopsy will enabled
sampling the healing area induced by the first biopsy. By selecting a punch size two
millimeters wider and taking a sample concentric to the first one, we can assure complete
removal of the area of interest.
Group 3: a second biopsy will be taken on day 6, respectively, in a similar way as described
for Group 2; pictures will be taken according to the Timetable.
Skin samples: In parallel to the oral biopsies, skin biopsies of similar size and depth as
the oral biopsy from the same subjects will be obtained from the axillary region following
the same schedule and procedure, including a second biopsy for groups 2 and 3.
Wounds will be photographed with a digital camera and the healing monitored at clinic visits
per schedule above. The excised tissues in each case will be immediately bisected on ice;
half of the sample will be fixed in 4% formaldehyde/PBS and embedded in paraffin for standard
histology and immunohistochemistry, and the remaining half will be placed in OCT-filled
plastic base molds, flash frozen in liquid nitrogen, and stored at 80 (Infinite)C until
processed for genomic and proteomic analysis.
Two important properties distinguish the process of healing of oral mucosa wounds from those
of the skin: more rapid healing and the absence of scar tissue formation. This is remarkable
given the apparent similarities of the two tissues. There are, however, prominent differences
in the healing environment, such as hydration, growth factor availability, inflammatory
response, and microbial exposure. Knowledge as to the causal contribution of each of these
factors to the differential healing response of the two epithelia is mostly anecdotal, and
oral wound healing has generally been poorly studied. This study seeks to provide a global
molecular definition of oral wound healing in comparison to that of the skin. The overall aim
will be to identify the specific factors that enable rapid and nearly scar-free healing of
oral mucosa. Identification of these physiological and molecular determinants will have
widespread implications for human oral health. Among others, it would provide venues for the
targeted exploration of procedures to accelerate the healing of critically-sized oral lesions
formed by trauma, surgery, radiation therapy, infection, and other oral pathologies, which,
if untreated, lead to permanent disability and dysfunction. Moreover, pathways and/or
molecules identified in these studies which may facilitate rapid, scar-less healing could be
considered for application to non-oral mucosal sites to promote healing and minimize
unsightly scars, which may also compromise the functional integrity of the tissue.
Hypotheses:
- There are significant differences in gene and protein expression between wound healing
in skin and oral mucosa.
- The recruitment of inflammatory cells associated with a large up-regulation of
inflammation-associated genes, including cytokines and chemokines, in the epithelial
cells of skin wounds may account for these differences.
- There are specific gene programs that can explain the presence of significant scarring
in skin tissues but not in oral mucosa.
OBJECTIVES:
The overall objective of this pilot study proposal is to establish the gene and protein
expression profiles during the early stages (1-6 days) of normal oral wound repair. By
comparing these profiles with those of cutaneous wound healing, we may be able to identify
molecules exclusive to oral wound repair that could represent biomarkers of the healing
process or serve as new therapeutic targets in pathological wound healing and cancer. One
specific hypothesis to be tested is that the level of expression of pro-inflammatory gene
networks by wound-infiltrating keratinocytes constitutes the most significant difference
between the human oral and cutaneous wound transcriptomes. The specific hypothesis has been
developed from data obtained from our recent complementary oral and skin wound healing
studies in animals.
ELIGIBILITY:
Healthy male volunteers age 18 to 40 will be enrolled in this study.
DESIGN:
Oral mucosa samples: A sterile 3-mm dermal punch will be used to create uniform,
full-thickness biopsy in the mucosa of the cheek just above the occlusal plane. Circular
pieces of tissue of approximately 2 mm in depth will be removed on the day of biopsy (day 1).
These subjects will be subsequently be randomly grouped as follows:
Group 1: no further samples will be collected; pictures will be taken on days 3, 6, 9, 13,
and 15 (see Timetable). This group will help document the normal healing process under the
conditions of the present study, including the lack of scaring in the area selected for the
initial wound in the oral mucosa as compared with the skin.
Group 2: a second biopsy will be taken on day 3, which will include the area of the first
biopsy with sterile 5 mm punch, following the same procedure as described for day 0; pictures
will be taken according to the schedule set in the Timetable. This second biopsy will enabled
sampling the healing area induced by the first biopsy. By selecting a punch size two
millimeters wider and taking a sample concentric to the first one, we can assure complete
removal of the area of interest.
Group 3: a second biopsy will be taken on day 6, respectively, in a similar way as described
for Group 2; pictures will be taken according to the Timetable.
Skin samples: In parallel to the oral biopsies, skin biopsies of similar size and depth as
the oral biopsy from the same subjects will be obtained from the axillary region following
the same schedule and procedure, including a second biopsy for groups 2 and 3.
Wounds will be photographed with a digital camera and the healing monitored at clinic visits
per schedule above. The excised tissues in each case will be immediately bisected on ice;
half of the sample will be fixed in 4% formaldehyde/PBS and embedded in paraffin for standard
histology and immunohistochemistry, and the remaining half will be placed in OCT-filled
plastic base molds, flash frozen in liquid nitrogen, and stored at 80 (Infinite)C until
processed for genomic and proteomic analysis.
- INCLUSION CRITERIA:
- Healthy male volunteers age 18 to 40.
- All volunteers must sign informed consent indicating their understanding that
specimens and demographic information will be collected solely for research purposes.
EXCLUSION CRITERIA:
Subjects with known inflammatory, chronic, and infectious diseases. These conditions
include but are not limited to:
- Diabetes
- Heart failure
- Pulmonary disease
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Sarcoidosis
- Sj(SqrRoot)(Delta)grens syndrome
- Dermatomyositis
- Psoriasis
- Cellulitis
Patients with known bleeding disorders or conditions associated with bleeding. These
conditions include but are not limited to:
- Hemophilia
- von Willebrand disease
- Protein C/S deficiency
- Antithrombin III deficiency
- Liver disease
- Patients on medications that interfere with blood clotting or blood thinners. These
medications include but are not limited to: ibuprofen aspirin, warfarin (Coumadin),
ticlopidine (Ticlid), clopidogrel (Plavix), and others.
- Subjects with clinically significant abnormal laboratory values will be ineligible
Complete blood count (CBC)
Platelet level: <100 - >500/ 10(3)/mcL
Hemoglobin: <10; > 17.5gr/L
Hematocrit: <30; >51%
White blood cell count: <3; >12 10(3)/mcL
Partial thromboplastin time: <20; >42 sec
Prothrombin time: <10; >20 sec
C-reactive protein: > 4 mg/L
Erythrocyte sedimentation rate: >40 ml/h
- Recent unintentional weight loss of >10 lbs over the past 6 weeks prior to screening
- Have undergone general or oral surgery within the last 30 days
- Treated with systemic steroids in the past 12 months
- Subjects with a history of abnormal scar formation (i.e., keloids, hypertrophic
scarring)
- Subjects who have used tobacco products and/or betel nut within one month of the
screening evaluation. Tobacco products include cigarette, pipe, cigar, and chewing
tobacco
- Heavy drinkers defined as drinking greater than or equal to alcoholic drinks per day
- Subjects that, at the oral clinical examination, show any of the nonmalignant lesions
associated with heavy smoking/tobacco chewing will be excluded. These findings include
but are not limited to:
- Tooth stains
- abrasions
- smoker s melanosis
- acute necrotizing gingivitis
- burns
- erythematous or keratotic patches
- black hairy tongue
- nicotinic stomatitis
- palatal erosions
- Subjects with preneoplastic (leukoplakia, erythroplakia, submucous fibrosis) or
neoplastic lesions
- Subjects with known or suspected allergies or adverse reactions to any of the agents
used for skin preparation, local anesthesia, or pain control or with known or
suspected allergy or adverse reaction to Prolene (polypropylene) sutures
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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