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Infrared Light Activates TNF-B1

 

Activation of latent TGF-B1 by low-power laser in vitro correlates with increased TGF-B1 levels in laser-enhanced oral wound healing

 

Praveen R Arany, MDS; Ramakant S. Nayak, MDS; Seema Hallikerimath, MDS; Anil M. Limaye, PhD; Alka D. Kale, MDS; Paturu Kondaiah, PhD

 

Molecular Reproduction Development and Genetics, Indian Institute of Science, Bangalore Kamataka, India and

Department of ORal Maxillofacial Patholgoy, K.L.E.'s Institues of Dental Sciences, Begaum Karnataka, India

Copyright 2007 by the Wound Healing Society
 
Abstact
 
The term Laser "Photobiomodulation" was coined to encompass the pleiotropic effects of low-power lasers on biological processes. The purpose of this study was to investigate whether transforming growth factor (TGF)-B had a role in mediating the biological effects of low-power far-infrared laser irradiation. We assayed for in vitro activation using various biological forms of cell-secreted, recombinant, and serum latent TGF-B using the p3TP reporter and enzyme-linked immunosorbent assays. We demonstrate here that low-power lasers are capable of activating latent TGF-B1 and -B3 in vitro and, further, that it is capable of "priming" these complexes, making them more amenable to physiological activation present in the healing milieu. Using an in vivo oral tooth extraction-healing model, we observed an increased TGF-B1, but not B3, expression by immunohistochemistry immediately following laser irradiation while TGF-B3 expression was increased after 14 days, concomitant with an increased inflammatory infiltrate. All comparisons were performed between laser-irradiated wounds and nonirradiated wounds in each subject essentially using them as their own control (paired T-test p<0.05).  Low-power laser irradiation is capable of activating the latent TGF-B1 complex in vitro and its expression pattern in vivo suggests that TGF-B play a central role in mediating the accelerated healing response.


 


 
Niether UVA or UVB light rays are used in the Acne Light, Ance Wand or Skin Wand.  We all know the sun can damage our skin causing premature aging and even cancer but most of us don't know how or why.

It can be hard to know what to look for when you need to protect your skin as it's easy to get confused about which UV ray does what

It's easier to know how to protect yourself if you know what you're protecting yourself from.

The sun has 2 types of damaging UV, (ultraviolet), rays:
1. UVA
2. UVB

UVA:
Long-wave solar rays of 320-400 nanometers, (billionths of a meter). You're almost never safe from exposure to UVA rays as they can go through windows, light clothing and even your windshield, so if you're outside you're getting exposed to UVA rays.

UVA rays are responsible for aging. They are less likely than UVB to cause sunburn but UVA penetrates the skin more deeply, causing wrinkling and leathering of the skin.

Prolonged exposure of UVA cracks and shrinks the collagen and elastin of our skin.

Collagen makes up 75% of our skin and is the fibrous protein of skin, cartilage, bone, and other connective tissue. Along with elastin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging.

Elastin, is a protein in connective tissue that is elastic and allows the skin to resume it's shape after stretching or contracting.

When UVA rays damage these components of our skin it looses strength and elasticity thus causing wrinkles, sagging, leathery skin and... aging!

If that's not bad enough studies show that UVA not only exacerbates UVB's carcinogenic effects but may also directly induce some skin cancers, including melanomas.

UVB:
Short-wave solar rays of 290-320 nanometers.

UVB rays are more potent than UVA in producing sunburn. Therefore these rays are considered the main cause of skin cancers, (basal and squamous cell carcinomas and melanoma).

Sometimes called the "tanning ray", UVB rays stimulate the melanocyte cell, (located in the bottom layer of the skin), to produce the brown pigment melanin, producing a suntan as a defense against UV radiation.

So even if it's a cloudy day and you're driving in your car you're getting exposed to the harmful UV rays of the sun. That's why it's so important to prtoect your skin with sunscreen and UV protective clothing at all times, (especially if you're working, playing or vacationing outside).
Acne LED Light Studies

 Visible violet (blue) light, present in sunlight, in the range 405-420 nm activates a porphyrin (Coproporphyrin III) in Propionibacterium acnes which damages and ultimately kills the bacteria by releasing singlet oxygen. A total of 320 J/cm2 of light within this range renders the bacteria non viable . This part of the spectrum is just outside the ultraviolet and produces little if any tanning or sunburn.


Application of the light for 3 consecutive days has been shown to reduce the bacteria in the pores by 99.9%. Since there are few porphyrins naturally found in the skin, the treatment is believed safe except in patients with porphyria;[ .... The light is usually created by fluorescent lamps, bright LEDs or dichroic filament bulbs.


Treatment is often accompanied with application of red light which has been shown to activate ATP in human skin cells (essentially a photobiomodulation effect), and seems to improve response rates.

Overall improvements of on average 76% for 80% of patients occurs over 3 months; most studies show that it performs better than Benzoyl peroxide and the treatment is far better tolerated. However, approximately 10% of users see no improvement.
 

Combination blue (415 nm) and red (633 nm) LED phototherapy in the treatment of mild to severe acne vulgaris.

Goldberg DJ  Russell BA

Skin Laser & Surgery Specialists of New York/New Jersey, and Department of Dermatology, Mount Sinai School of Medicine, New York, NY 10022, USA. drdavidgoldberg@skinandlasers.com

BACKGROUND AND OBJECTIVE: Acne vulgaris represents both a challenge to the treating dermatologist and a major concern for the patient. Conventional treatments have proved inconsistent with often unacceptable side effects and high rates of recurrence. Non-thermal, non-laser, phototherapy for acne with a combination of blue and red light has recently attracted attention. The present study was designed to assess the efficacy of this combination phototherapy. METHODS: Twenty-four subjects, Fitzpatrick skin types II-V, with mild to severe symmetric facial acne vulgaris were recruited for the study. Subjects were well matched at baseline in terms of both age and duration of acne. Subjects were treated over eight sessions, two per week 3 days apart, alternating between 415 nm blue light (20 minutes/session, 48 J/cm2) and 633 nm red light (20 minutes/session, 96 J/cm2) from a light-emitting diode (LED)-based therapy system. Patients received a mild microdermabrasion before each session. Acne was assessed at baseline and at weeks 2, 4, 8 and 12. RESULTS: Twenty-two patients completed the trial. A mean reduction in lesion count was observed at all follow-up points. At the 4-week follow-up, the mean lesion count reduction was significant at 46% (p=0.001). At the 12-week follow-up, the mean lesion count reduction was also significant at 81% (p=0.001). Patient and dermatologist assessments were similar. Severe acne showed a marginally better response than mild acne. Side effects were minimal and transitory. Comedones did not respond as well as inflammatory lesions. CONCLUSIONS: Combination blue and red LED therapy appears to have excellent potential in the treatment of mild to severe acne. Treatment appears to be both pain- and side effect-free.

PMID: 16766484 [PubMed - indexed for MEDLINE]
 
 

Blue light phototherapy in the treatment of acne.

Author: Tzung TY, Wu KH, Huang ML

Author affiliation: Department of Dermatology, Veterans General Hospital Kaohsiung, 386 Ta-Chung 1st Road, Kaohsiung 813, Taiwan. tytzung@isca.vghks.gov.tw

Publication date & source: 2004.10, Photodermatol Photoimmunol Photomed., 20(5):266-9.

Publication type: Clinical Trial; Randomized Controlled Trial

 

BACKGROUND: Blue light irradiation is known to be effective against acne. However, the profile of a good candidate is still unclear. METHODS: Thirty-one Taiwanese with symmetrical facial acne were irradiated with blue light on one side of the face selected randomly twice weekly for 4 consecutive weeks. The other half of the face was left untreated as control. Parameters, including scar type, pore size, and facial follicular porphyrin fluorescence intensity, were documented. The severity of acne was assessed before the treatment, after two, four, and eight sessions of treatment, and 1 month after the treatment was completed. RESULTS: Compared with the non-irradiation side, eight sessions of blue light irradiation were effective in acne treatment (P<0.001). Gender (P=0.471), scar type (P-values of pitted, atrophic, and hypertrophic type were 0.688, 0.572, and 0.802, respectively), pore size (P=0.755), and pretreatment fluorescence intensity (P=0.656) could not be used as predictive factors of therapeutic effectiveness. Compared with pretreatment, nodulocystic lesions tended to worsen despite treatment. In addition, the therapeutic effectiveness was not related to the fluorescence intensity change (P=0.812). CONCLUSIONS: Blue light irradiation is effective in acne treatment. Patients without nodulocystic lesions are better candidates for blue light irradiation.

 

 
LIGHT-EMITTING DIODE (LED): COMBINED 633 NM AND 830 NM LED TREATMENT OF FACIAL PHOTOAGING
 

During 2007, Lee et al of Korea , have demonstrated that LED is effective for non-ablative facial skin rejuvenation. David Goldberg from the United States , and working independently, published data on facial photo rejuvenation in Annals of Drugs in Dermatology 2006. (See www.encyclopedia.com ). Their group studied the efficacy of and ultra structural changes in photo-aged skins after combined 633 nm and 830 nm LED treatment (Omnilux TM ). Results from that study showed:

  1. Statistical and objective improvement in wrinkles was detectable and the skin was rendered soft, smooth and firm in a high proportion of cases.
  2. Skin biopsies and EM showed deposition of collagen fibres. This confirmed the finding of post-LED treatment dermal thickening by collagen.
  3. LED can be used either as a primary or adjunctive treatment modality for facial rejuvenation, and can ameliorate wrinkles.
  4. They used the Glogau scale to select patients and gauge aging.
  5. Fitzpatrick skin grading was also used to select clients for the trial.
  6. The Omnilux Revive (TM) and Omnilux Plus (TM) were used. The one delivers noncoherent but quasimonochromatic red light at a wavelength of 633 nm and an intensity of 105 mW/cm 2 for a total of 126 J/cm 2 after 20 minutes of exposure. The other light-head delivers noncoherent light at a wavelength of 830 nm and 55 mW/cm 2 intensity for a total dose of 66 J/cm 2 after 20 minutes exposure. Skin furrowing as determined by profilometry was significantly reduced. Photoaging assessment scores after treatment also improved. Most patients reported softening of periorbital wrinkles. All reported improved skin softness, smoothness and firmness. Very few minor side effects were recorded and no down-time. LED has a far safer treatment profile than ablative methodologies for skin rejuvenation such as aggressive chemical peels and laser resurfacing.

According to the work of Goldberg and co-researchers, LED therapy involves the absorption of a specific wavelength of light by a photo-acceptor molecule. Irradiation of the photo-acceptor generates production of cytotoxic singlet oxygen. A cascade of cellular responses is thus initiated, resulting in modulation of cell function, cell proliferation and repair of compromised cells (Karu et al 1987; Karu et al 1989). The process of cell function enhancement is called photobiomodulation . Radiation of fibroblasts with 633 nm wavelength light increases procollagen synthesis fourfold from baseline. Irradiation with this red light increases fibroblastic growth factor synthesis from photoactivated macrophages and accelerated mast cell degranulation (Glogau et al 1996).

Other studies have indicated that LED 630 to 700 nm penetrates tissue to a depth of about 10 mm (see www.elixa.com ). This proves useful for the wound healing of cuts, scars, trigger and acupuncture points, and low grade soft tissue infections.

Other eminent workers in the field include Glen Calderhead of Japan who has a great understanding of the mechanism of photobiomodulation, and published widely in the field.

Non-ablative skin rejuvenation is divided into thermal (photo-thermal reaction i.e. controlled thermal damage to invoke a wound healing process) and photobiomodulation (i.e. LED stimulates cell activities and cell proliferation). The key components of photobiomodulation include:

  • Fibroblast proliferation.
  • Synthesis of collagen and procollagen.
  • Growth factor production (i.e. TGF, PDGF).
  • Macrophage and lymphocyte stimulation.
  • Extra cellular matrix production.
  • Improvement of microcirculation.

TREATMENT OF FACIAL PHOTOAGING WITH LED THERAPY:

  • LED is better for prevention than curing of late face solar changes.
  • LED is a good adjunct to microdermabrasion, peels, IPL and lasers.
  • A younger skin responds better to LED photobiomodulation.
  • Narrow band 830 nm and 633 nm are effective for non-ablative skin rejuvenation.

WAVELENGTH-SPECIFIC ACTIONS OF LIGHT ON TARGETED CELLS

 

Mast

Leukocyte

Macrophage

Fibroblast

Myofibroblast

633

++

+

++

+++

+

830

+++

+++

+++

+

+++

INFLAMMATORY CASCADE: WOUND HEALING CONCEPTS

  • In the inflammatory phase, 830 nm is effective on monocytes, mast cells and macrophages.
  • In the proliferation phase, 633 nm is functional.
  • In the remodeling phase, 830 nm stimulates fibrocytes, endotheliocytes, fibroblasts and myofibroblasts.

METABOLIC AND BIOCHEMICAL EFFECTS: MOLECULAR COMPONENTS AFTER LED TREATMENT: SEE LEE (et al 2007).

  • ADP
  • ATP
  • Ca ++
  • NAD
  • NAD + and H +
  • Na + K + ATPase
  • TIMP-1
  • IL-6
  • TNF-a
  • ICam-L
  • Connexion-43
  • Reduced IL-6

EFFECTS OF LED ON THE FACIAL SKIN: OUTCOMES:

  1. Reduced melasma and chloasma.
  2. Improved skin texture and tone if combined with Neostrata glycolic acid peel.
  3. Lightening of cavernous haemangioma (but not cure).
  4. Reduced facial pigmentation.
  5. Reduction of moderate wrinkles, horizontal and vertical crepe lines of the face and décolleté.
  6. Can be combined with Botox in young persons: athermal process
  7. Histology: Biopsy studies demonstrate increased deposition of collagen and elastin (MT stains, von Giesson and Alcian blue stains).
  8. EM: showed fibroblast proliferation and release of collagen.
  9. There is thus clinical and histological evidence to confirm improvement of the aged skin after LED phototherapy. The rejuvenation of the skin after LED phototherapy is safe and predictable. The rejuvenation of the skin is based on the following hypothesis:
  • Activation of fibroblasts.
  • Induction of TIMP-1 and 2
  • Inhibition of MMP activities on new collagen.
  • Increase in the mRNA levels of IL-1 ß , TNF- a and Connexion 43.
  • Wound healing by activation of (IL-1 ß and TNF- a).
  • Propagation of cellular responses through GJIC.

CLINICAL APPLICATION OF LED IN THE CLINIC: WOUND HEALING

  1. Wound healing (reduction of wound scars, mammoreduction, blepharoplasty, sutured wounds).
  2. Aesthetic: skin rejuvenation.
  3. Acne (use alternating blue and red LED irradiation).
  4. Indolent sole ulcers (diabetic and non-diabetic).
  5. Sacral sores (indolent).
  6. Treatment of cellulite (see Sasaki et al, J Cosm Laser Ther , 2007: 9:87-96).

BOLANDCELL ACADEMIC REFERENCES: OCTOBER 2007

  1. Lee et al : A prospective, randomized, placebo-controlled, double blinded and split-face clinical study on LED phototherapy for skin rejuvenation. J Photochem and Photobiology, 88 ( 2007), 51-67.
  2. Goldberg DJ. New collagen formation after dermal remodeling with an intense pulsed light source. J Cutan Laser Ther, (2) ( 2000): 59-61.
  3. Calderhead RG et al: Phototherapy unveiled.. Laser Therapy 2005; 14;87-95

Titre du document / Document title

Transforming growth Factory-β1-Induced collagen production in cultures of cardiac fibroblasts is the result of the appearance of myofibroblasts

Auteur(s) / Author(s)

LIJNEN P. (1) ; PETROV V. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, Faculty of Medicine, University of Leuven, Leuven, BELGIQUE

Résumé / Abstract

Transforming growth factor-β1 (TGF-β1), which appears in high concentrations in fibrotic cardiac tissue, is a potent inductor of tissue collagen deposition and of the differentiation of fibroblasts to myofibroblasts. It is accepted that TGF-β1 is a potent stimulator of collagen secretion by fibroblasts. The aim of the present study was to determine which type of cells, fibroblasts and/or myofibroblasts are stimulated, in terms of collagen production, by TGF-β1. Therefore, using cultures of second-passage rat cardiac fibroblasts. we investigated the dose-(0.003-15 ng/ml) and time-depen deuce (2-48 h) of the TGF-β1-induced effects on collagen production and on the appearance of myofibroblasts, as estimated by the presence of α-smooth muscle actin (α-SMA; a marker of myofibroblasts). The reversibility of the TGF-β1-stimulated effects was also studied. The dose-and time-dependent stimulation of collagen production was closely associated with the induction of α-SMA, TGF-β1 did not change the cell phenotype or increase collagen production in rat cardiac fibroblasts cultures after a long incubation (24-28 h) at low concentrations (< I ng/ml), or after a short incubation (2-4 h) at high concentrations (1-15 ng/ml). However, after a long incubation at high concentrations, TGF-β1 changed the cell phenotype and increased collagen production in these cultures through the differentiation of fibroblasts to myofibroblasts. A maximal increase of collagen production (two-fold p < 0.001) was observed after incubation of fibroblasts with IS ng/ml TGF-β1 for 48 h. Under these conditions, α-SMA was increased by 3.5-fold (p < 0.001) and second-passage cultures of fibroblasts and their offspring in the next passage consisted mainly of myofibroblasts. The stimulation of collagen by 15 ng/ml TGF-β1 for 48 h was irreversible. In fact, additional incubation of these second-passage TGF-β1-stimulated cultures without TGF-β1 for 2 days did not decrese the high activity of collagen production. Moreover, the third-passage offspring of these TGF-β1-stimulated fibroblasts cultured without TGF-β1 also showed a higher production of collagen compared with control fibroblasts. Furthermore, the increased collagen production in the third-passage fibroblast offspring of the second-passage TGF-β1-stimulated fibroblasts could not be further stimulated by TGF-β1. Thus, the activity of collagen production in TGF-β1-stimulated cultures and in their next passage offspring it not sensitive to TGF-β1. Our data suggest that TGF-β1-stimulated collagen production in cultures of adult rat cardiac ventricular fibroblasts cannot be explained by a direct stimulation of collagen production, either in fibroblasts or in myofibroblasts. Instead, TGF-β1 induces differentiation of fibroblasts to myofibroblasts, the latter having a higher activity for collagen production than the former.

Revue / Journal Title

Methods and findings in experimental and clinical pharmacology   ISSN 0379-0355 

Source / Source

2002, vol. 24, no6, pp. 333-344 (45 ref.)

Langue / Language

Anglais

Editeur / Publisher

Prous, Barcelona, ESPAGNE  (1979) (Revue)

Mots-clés anglais / English Keywords

Vertebrata ; Mammalia ; Rodentia ; In vitro ; Cell culture ; Actin ; Rat ; Cell differentiation ; Myofibroblast ; Circulatory system ; Heart ; Fibroblast ; Collagen ; Cytokine ; Transforming growth factor β1 ;

Mots-clés français / French Keywords

Vertebrata ; Mammalia ; Rodentia ; In vitro ; Culture cellulaire ; Actine ; Rat ; Cytodifférenciation ; Myofibroblaste ; Appareil circulatoire ; Coeur ; Fibroblaste ; Collagène ; Cytokine ; Facteur croissance transformant β1 ;

Mots-clés espagnols / Spanish Keywords

Vertebrata ; Mammalia ; Rodentia ; In vitro ; Cultivo celular ; Actina ; Rata ; Diferenciación celular ; Miofibroblasto ; Aparato circulatorio ; Corazón ; Fibroblasto ; Colágeno ; Citoquina ; Factor crecimiento transformante β1 ;

Localisation / Location

INIST-CNRS, Cote INIST : 18217, 35400010446921.0010

Copyright 2008 INIST-CNRS. All rights reserved
Toute reproduction ou diffusion même partielle, par quelque procédé ou sur tout support que ce soit, ne pourra être faite sans l'accord préalable écrit de l'INIST-CNRS.
No part of these records may be reproduced of distributed, in any form or by any means, without the prior written permission of INIST-CNRS.
Nº notice refdoc (ud4) : 13831425
NASA Supported Study

The NASA Light-Emitting Diode Medical Program – Progress in Space Flight and Terrestrial Applications

Harry T. Whelan, M.D.1a,2,3, John M Houle, B.S.1a,

Noel T. Whelan1a,3, Deborah L. Donohoe, A.S., L.A.T.G.1a,

Joan Cwiklinski, M.S.N., C.P.N.P.1a, Meic H. Schmidt, M.D.1c,

Lisa Gould, M.D., PhD.1b, David Larson, M.D.1b,

Glenn A. Meyer, M.D.1a, Vita Cevenini3, Helen Stinson, B.S.3

1a Departments of Neurology, 1bPlastic Surgery and 1cNeurosurgery,

Medical College of Wisconsin, Milwaukee, WI 53226, (414) 456-4090

2Naval Special Warfare Group TWO, Norfolk, VA 23521, (757) 462-7759

3NASA-Marshall Space Flight Center, AL 35812, (256) 544-2121

 

Abstract. This work is supported and managed through the NASA Marshall Space Flight Center – SBIR Program. Studies on cells exposed to microgravity and hypergravity indicate that human cells need gravity to stimulate cell growth. As the gravitational force increases or decreases, the cell function responds in a linear fashion. This poses significant health risks for astronauts in long term space flight. LED-technology developed for NASA plant grown experiments in space shows promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. This LED-technology is also biologically optimal for photodynamic therapy of cancer.

 

LED-ENHANCEMENT OF CELL GROWTH

The application of light therapy with the use of NASA LED’s will significantly improve the medical care that is available to astronauts on long-term space missions. NASA LED’s stimulate the basic energy processes in the mitochondria (energy compartments) of each cell, particularly when near-infrared light is used to activate the color sensitive chemicals (chromophores, cytochrome systems) inside. Optimal LED wavelengths include 680, 730 and 880 nm. The depth of near-infrared light penetration into human tissue has been measured spectroscopically (Chance, et al 1988). Spectra taken from the wrist flexor muscles in the forearm and muscles in the calf of the leg demonstrate that most of the light photons at wavelengths between 630-800 nm travel 23 cm through the surface tissue and muscle between input and exit at the photon detector. Our laboratory has improved the healing of wounds in laboratory animals by using NASA LED light and hyperbaric oxygen. Furthermore, DNA synthesis in fibroblasts and muscle cells has been quintupled using NASA LED light alone, in a single application combining 680, 730, and 880 nm each at 4 Joules per centimeter squared.

Muscle and bone atrophy are well documented in astronauts, and various minor injuries occurring in space have been reported not to heal until landing on Earth. Long term space flight, with its many inherent risks, also raises the possibility of astronauts being injured performing their required tasks. The fact that the normal healing process is negatively affected by microgravity requires novel approaches to improve wound healing and tissue growth in space. NASA LED arrays have already flown on Space Shuttle missions for studies of plant growth. The U.S. Food and Drug Administration (FDA) has approved human trials. The use of light therapy with LED’s is an approach to help increase the rate of wound healing in the microgravity environment, reducing the risk of treatable injuries becoming mission catastrophes.

Wounds heal less effectively in space than here on Earth. Improved wound healing may have multiple applications which benefit civilian medical care, military situations and long-term space flight. Laser light and hyperbaric oxygen have been widely acclaimed to speed wound healing in ischemic, hypoxic wounds. An excellent review of recent human experience with near-infrared light therapy for wound healing was published by Conlan, et al in 1996. Lasers provide low energy stimulation of tissues which results in increased cellular activity during wound healing (Beauvoit, 1989, 1995; Eggert, 1993; Karu, 1989; Lubart, 1992, 1997; Salansky, 1998; Whelan, 1999; Yu, 1997). Some of these activities include increased fibroblast proliferation, growth factor syntheses, collagen production and angiogenesis. Lasers, however, have some inherent characteristics, which make their use in a clinical setting problematic, including limitations in wavelengths and beam width. The combined wavelengths of light optimal for wound healing cannot be efficiently produced, and the size of wounds which may be treated by lasers is limited. Light-emitting diodes (LED’s) offer an effective alternative to lasers. These diodes can be made to produce multiple wavelengths, and can be arranged in large, flat arrays allowing treatment of large wounds. Our experiments suggest potential for using LED light therapy at 680, 730 and 880 nm simultaneously, alone and in combination with hyperbaric oxygen therapy, both alone and in combination, to accelerate the healing process in Space Station Missions, where prolonged exposure to microgravity may otherwise retard healing. NASA LED’s have proven to stimulate wound healing at near-infrared wavelengths of 680, 730 and 880 nm in laboratory animals, and have been approved by the U.S. Food and Drug Administration (FDA) for human trials. Furthermore, near-infrared LED light has quintupled the growth of fibroblasts and muscle cells in tissue culture. The NASA LED arrays are light enough and mobile enough to have already flown on the Space Shuttle numerous times. LED arrays may prove to be useful for improving wound healing and treating problem wounds, as well as speeding the return of deconditioned personnel to full duty performance. Potential benefits to NASA, military, and civilian populations include treatment of serious burns, crush injuries, non-healing fractures, muscle and bone atrophy, traumatic ischemic wounds, radiation tissue damage, compromised skin grafts, and tissue regeneration.
 

Wound Healing, Healing and Repair

Michael Mercandetti, MD, MBA, FACS, Consulting Staff, Department of Surgery, Doctors Hospital of Sarasota
Adam J Cohen, MD, Assistant Professor, Department of Ophthalmology, Northwestern University Feinberg School of Medicine; Consulting Surgeon, Myers Wyse Center for the Eye; Director, Center for Facial Rejuvenation; Founding Partner, HC Consulting, Inc

Updated: Mar 27, 2008

Introduction

Wound healing is a complex and dynamic process of restoring cellular structures and tissue layers. The human adult wound healing process can be divided into 3 distinct phases: the inflammatory phase, the proliferative phase, and the remodeling phase. Within these 3 broad phases is a complex and coordinated series of events that includes chemotaxis, phagocytosis, neocollagenesis, collagen degradation, and collagen remodeling. In addition, angiogenesis, epithelization, and the production of new glycosaminoglycans (GAGs) and proteoglycans are vital to the wound healing milieu. The culmination of these biological processes results in the replacement of normal skin structures with fibroblastic mediated scar tissue. For more information on wound healing, visit Medscape's Wound Management Resource Center.

 

This process can go awry and produce an exuberance of fibroblastic proliferation with a resultant hypertrophic scar, which by definition is confined to the wound site. Further exuberance can result in keloid formation, where scar production extends beyond the area of the original insult. Conversely, insufficient healing can result in atrophic scar formation. Click here to complete a CME activity on evidence-based medicine in wound care.

Types of Wound Healing

Although various categories of wound healing have been described, the ultimate outcome of any healing process is repair of a tissue defect.

 

Primary healing, delayed primary healing, and healing by secondary intention are the 3 main categories of wound healing. Even though different categories exist, the interactions of cellular and extracellular constituents are similar.

 

A fourth category is healing that transpires with wounds that are only partial skin thickness.1

Categories of Wound Healing

Category 1

Primary wound healing or healing by first intention occurs within hours of repairing a full-thickness surgical incision. This surgical insult results in the mortality of a minimal number of cellular constituents.

 

Category 2

If the wound edges are not reapproximated immediately, delayed primary wound healing transpires. This type of healing may be desired in the case of contaminated wounds. By the fourth day, phagocytosis of contaminated tissues is well underway, and the processes of epithelization, collagen deposition, and maturation are occurring. Foreign materials are walled off by macrophages that may metamorphose into epithelioid cells, which are encircled by mononuclear leukocytes, forming granulomas. Usually the wound is closed surgically at this juncture, and if the "cleansing" of the wound is incomplete, chronic inflammation can ensue, resulting in prominent scarring.

 

Category 3

A third type of healing is known as secondary healing or healing by secondary intention. In this type of healing, a full-thickness wound is allowed to close and heal. Secondary healing results in an inflammatory response that is more intense than with primary wound healing. In addition, a larger quantity of granulomatous tissue is fabricated because of the need for wound closure. Secondary healing results in pronounced contraction of wounds. Fibroblastic differentiation into myofibroblasts, which resemble contractile smooth muscle, is believed to contribute to wound contraction. These myofibroblasts are maximally present in the wound from the 10th-21st days.

 

Category 4

Epithelization is the process by which epithelial cells migrate and replicate via mitosis and traverse the wound. This occurs as part of the phases of wound healing, which are discussed in Sequence of Events in Wound Healing. In wounds that are partial thickness, involving only the epidermis and superficial dermis, epithelization is the predominant method by which healing occurs. Wound contracture is not a common component of this process if only the epidermis or epidermis and superficial dermis are involved.

Overview of Wound Healing

The amalgam of coordinated events that constitute the process of wound healing is quite complex. The steps in the procession of wound healing include inflammation, the fibroblastic phase, scar maturation, and wound contracture.2, 3 Wound contracture is a process that occurs throughout the healing process, commencing in the fibroblastic stage.2

 

The inflammatory phase occurs immediately following the injury and lasts approximately 6 days. The fibroblastic phase occurs at the termination of the inflammatory phase and can last up to 4 weeks. Scar maturation begins at the fourth week and can last for years.2

 

An analogous system depicts the 4 phases as hemostasis, inflammation, granulation, and remodeling in a continuous symbiotic process.4 This is the phase system used in this text.

Sequence of Events in Wound Healing

Following tissue injury via an incision, the initial response is usually bleeding. The cascade of vasoconstriction and coagulation commences with clotted blood immediately impregnating the wound, leading to hemostasis, and with dehydration, a scab forms. An influx of inflammatory cells follows, with the release of cellular substances and mediators. Angiogenesis and re-epithelization occur and the deposition of new cellular and extracellular components ensues.

 

Initial phase - Hemostasis

Following vasoconstriction, platelets adhere to damaged endothelium and discharge adenosine diphosphate (ADP), promoting thrombocyte clumping, which dams the wound. The inflammatory phase is initiated by the release of numerous cytokines by platelets. Alpha granules liberate platelet-derived growth factor (PDGF), platelet factor IV, and transforming growth factor beta (TGF-b), while vasoactive amines such as histamine and serotonin are released from dense bodies found in thrombocytes. PDGF is chemotactic for fibroblasts and, along with TGF-b, is a potent modulator of fibroblastic mitosis, leading to prolific collagen fibril construction in later phases. Fibrinogen is cleaved into fibrin and the framework for completion of the coagulation process is formed. Fibrin provides the structural support for cellular constituents of inflammation. This process starts immediately after the insult and may continue for a few days.

 

Second phase - Inflammation

Within the first 6-8 hours, the next phase of the healing process is underway, with polymorphonuclear leukocytes (PMNs) engorging the wound. TGF-b facilitates PMN migration from surrounding blood vessels where they extrude themselves from these vessels. These cells "cleanse" the wound, clearing it of debris. The PMNs attain their maximal numbers in 24-48 hours and commence their departure by hour 72. Other chemotactic agents are released, including fibroblastic growth factor (FGF), transforming growth factors (TGF-b and TGF-a), PDGF, and plasma-activated complements C3a and C5a (anaphylactic toxins). They are sequestered by macrophages or interred within the scab or eschar.5

 

As the process continues, monocytes also exude from the vessels. These are termed macrophages. The macrophages continue the cleansing process and manufacture various growth factors during days 3-4. The macrophages orchestrate the multiplication of endothelial cells with the sprouting of new blood vessels, the duplication of smooth muscle cells, and the creation of the milieu created by the fibroblast. Many factors influencing the wound healing process are secreted by macrophages. These include TGFs, cytokines and interleukin-1 (IL-1), tumor necrosis factor (TNF), and PDGF.

 

Third phase - Granulation

This phase consists of different subphases. These subphases do not happen in discrete time frames but constitute an overall and ongoing process. The subphases are "fibroplasia, matrix deposition, angiogenesis and re-epithelialization".4

 

In days 5-7, fibroblasts have migrated into the wound, laying down new collagen of the subtypes I and III. Early in normal wound healing, type III collagen predominates but is later replaced by type I collagen.

 

Tropocollagen is the precursor of all collagen types and is transformed within the cell's rough endoplasmic reticulum, where proline and lysine are hydroxylated. Disulfide bonds are established, allowing 3 tropocollagen strands to form a triple left-handed triple helix, termed procollagen. As the procollagen is secreted into the extracellular space, peptidases in the cell wall cleave terminal peptide chains, creating true collagen fibrils.

 

The wound is suffused with GAGs and fibronectin produced by fibroblasts. These GAGs include heparan sulfate, hyaluronic acid, chondroitin sulfate, and keratan sulfate. Proteoglycans are GAGs that are bonded covalently to a protein core and contribute to matrix deposition.

 

Angiogenesis is the product of parent vessel offshoots. The formation of new vasculature requires extracellular matrix and basement membrane degradation followed by migration, mitosis, and maturation of endothelial cells. Basic FGF and vascular endothelial growth factor are believed to modulate angiogenesis.

 

Re-epithelization occurs with the migration of cells from the periphery of the wound and adnexal structures. This process commences with the spreading of cells within 24 hours. Division of peripheral cells occurs in hours 48-72, resulting in a thin epithelial cell layer, which bridges the wound. Epidermal growth factors are believed to play a key role in this aspect of wound healing.

 

This succession of subphases can last up to 4 weeks in the clean and uncontaminated wound.

 

Fourth phase - Remodeling

After the third week, the wound undergoes constant alterations, known as remodeling, which can last for years after the initial injury occurred. Collagen is degraded and deposited in an equilibrium-producing fashion, resulting in no change in the amount of collagen present in the wound. The collagen deposition in normal wound healing reaches a peak by the third week after the wound is created. Contraction of the wound is an ongoing process resulting in part from the proliferation of the specialized fibroblasts termed myofibroblasts, which resemble contractile smooth muscle cells. Wound contraction occurs to a greater extent with secondary healing than with primary healing. Maximal tensile strength of the wound is achieved by the 12th week, and the ultimate resultant scar has only 80% of the tensile strength of the original skin that it has replaced.

Summary

The process of wound healing constitutes an array of interrelated and concomitant events.

Future and Controversies

Future advances in wound healing will focus on affecting the agents that influence the processes involved in the repair of damaged tissue. Laser techniques, nonlaser techniques, and other modalities are being explored to enhance the proliferation of cells, the migration of cells, and the acceleration of the healing of wounds.6, 7

References

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  2. Tanenbaum M. Skin and tissue techniques. In: McCord CD Jr, Tanenbaum M, Nunery WR, eds. Oculoplastic Surgery. 3rd ed. 1995:3-4.

  3. Cahill KV, Carroll RP. Principles, techniques, and instruments. In: Stewart WB, ed. Surgery of the Eyelid, Orbit, and Lacrimal System. Vol 1. 1993:10-11.

  4. Cho CY, Lo JS. Dressing the part. Dermatol Clin. Jan 1998;16(1):25-47. [Medline].

  5. Habif TP. Dermatologic surgical procedures. In: Clinic Dermatology: A Color Guide to Diagnosis and Therapy. 3rd ed. 1996:809-810.

  6. Hawkins D, Abrahamse H. Influence of broad-spectrum and infrared light in combination with laser irradiation on the proliferation of wounded skin fibroblasts. Photomed Laser Surg. Jun 2007;25(3):159-69. [Medline].

  7. Hawkins DH, Abrahamse H. The role of laser fluence in cell viability, proliferation, and membrane integrity of wounded human skin fibroblasts following helium-neon laser irradiation. Lasers Surg Med. Jan 2006;38(1):74-83. [Medline].

  8. Aukhil I. Biology of wound healing. Periodontol 2000. Feb 2000;22:44-50. [Medline].

  9. Bennett NT, Schultz GS. Growth factors and wound healing: Part II. Role in normal and chronic wound healing. Am J Surg. Jul 1993;166(1):74-81. [Medline].

  10. Bock O, Yu H, Zitron S, Bayat A, Ferguson MW, Mrowietz U. Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblast of keloids and hypertrophic scars. Acta Derm Venereol. 2005;85(3):216-20. [Medline].

  11. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med. Nov 10 1994;331(19):1286-92. [Medline].

  12. Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. Apr 2001;69(4):513-21. [Medline].

  13. Kumar V, Ramzi CS, Robbins SL. Chapters 1-3. In: Basic Pathology. 5th ed. 1992:3-60.

  14. Peled ZM, Chin GS, Liu W, Galliano R, Longaker MT. Response to tissue injury. Clin Plast Surg. Oct 2000;27(4):489-500. [Medline].

  15. Quan G, Choi JY, Lee DS, Lee SC. TGF-beta1 up-regulates transglutaminase two and fibronectin in dermal fibroblasts: a possible mechanism for the stabilization of tissue inflammation. Arch Dermatol Res. Aug 2005;297(2):84-90. [Medline].

Keywords

healing, wound healing, wound repair, phases of healing, inflammatory phase, proliferative phase, remodeling phase, chemotaxis, phagocytosis, neocollagenesis, collagen degradation, collagen remodeling, angiogenesis, epithelization, glycosaminoglycans, GAGs, proteoglycans

Contributor Information and Disclosures

Author

Michael Mercandetti, MD, MBA, FACS, Consulting Staff, Department of Surgery, Doctors Hospital of Sarasota
Michael Mercandetti, MD, MBA, FACS is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Ophthalmology, American College of Surgeons, American Society for Laser Medicine and Surgery, American Society of Ophthalmic Plastic and Reconstructive Surgery, Association of Military Surgeons of the US, and Sarasota County Medical Society
Disclosure: Nothing to disclose

Coauthor

Adam J Cohen, MD, Assistant Professor, Department of Ophthalmology, Northwestern University Feinberg School of Medicine; Consulting Surgeon, Myers Wyse Center for the Eye; Director, Center for Facial Rejuvenation; Founding Partner, HC Consulting, Inc
Adam J Cohen, MD is a member of the following medical societies: American Academy of Ophthalmology and American College of Surgeons
Disclosure: Nothing to disclose