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Cl K, Jeyaraman M, Jeyaraman N, Ramasubramanian S, Khanna M, Yadav S. Antimicrobial Effects of Platelet-Rich Plasma and Platelet-Rich Fibrin: A Scoping Review. Cureus 2023; 15:e51360. [PMID: 38292974 PMCID: PMC10825076 DOI: 10.7759/cureus.51360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2023] [Indexed: 02/01/2024] Open
Abstract
Platelet-rich plasma (PRP), derived from the centrifugation and subsequent separation of whole blood, results in an unusually high concentration of platelets. A newer form of platelet concentrate, platelet-rich fibrin (PRF), has also been developed. There has been significant research into the therapeutic effects of PRP, particularly in enhancing wound healing and preventing infections in surgical wounds. This scoping review aims to thoroughly evaluate preclinical and clinical evidence regarding the antimicrobial effects of PRP and PRF. In conducting this review, 612 records were examined, and 36 articles were selected for inclusion. The studies reviewed include preclinical research, such as in-vitro and in-vivo studies, and clinical trials involving human participants. The current clinical evidence suggests a notable trend towards the antimicrobial capabilities of PRP and PRF, underscoring their potential benefits in treating wounds. The application of PRP and PRF in wound management shows encouraging outcomes, but further investigation is needed to optimize their use as antimicrobial agents. Additional research, particularly randomized controlled trials, is essential to substantiate their antimicrobial effectiveness in specific diseases and types of wounds, considering their potential impact on clinical results.
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Affiliation(s)
- Karan Cl
- Orthopaedics, Sanjay Gandhi Institute of Trauma & Orthopaedics, Bengaluru, IND
| | - Madhan Jeyaraman
- Orthopaedics, ACS Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai, IND
| | - Naveen Jeyaraman
- Orthopaedics, ACS Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai, IND
| | | | - Manish Khanna
- Orthopaedics, Autonomous State Medical College, Ayodhya, IND
| | - Sankalp Yadav
- Internal Medicine, Shri Madan Lal Khurana Chest Clinic, New Delhi, IND
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Cullen B, Gefen A. The biological and physiological impact of the performance of wound dressings. Int Wound J 2023; 20:1292-1303. [PMID: 36110054 PMCID: PMC10031231 DOI: 10.1111/iwj.13960] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 11/27/2022] Open
Abstract
Chronic wounds affect millions globally and are a huge financial burden. Whilst there are many wound dressings commercially available to manage these wounds, the complexity of the repair process makes it difficult to select the right dressing for the right wound at the right time. Thus, in this narrative review, we have examined reasons why wounds fail to heal, summarised the pathophysiology of the chronic wound environment and provided an evidence-based, clinically-relevant compilation of the published literature relevant to dressing design and evaluation. This has highlighted the need for a deeper understanding of wound exudates, how exudates change throughout the healing process, and how they are impacted by different dressing materials. Studies assessing biochemical and biophysical changes in exudates throughout the healing process are extremely valuable in this regard, enhancing both our understanding of the wound healing process and the ability to assess dressing performance. In addition, this knowledge allows us to replicate various wound conditions in the laboratory, and develop clinically-relevant models for testing current and new dressings, therefore providing a more comprehensive understanding of how and when they should be used. This approach makes the use of dressings more effective, thereby improving outcomes, and reducing the economic burden of chronic wounds.
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Affiliation(s)
| | - Amit Gefen
- Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel
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Rayate AS, Nagoba BS, Mumbre SS, Mavani HB, Gavkare AM, Deshpande AS. Current scenario of traditional medicines in management of diabetic foot ulcers: A review. World J Diabetes 2023; 14:1-16. [PMID: 36684382 PMCID: PMC9850800 DOI: 10.4239/wjd.v14.i1.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/04/2022] [Accepted: 12/06/2022] [Indexed: 01/10/2023] Open
Abstract
Diabetic foot infections and diabetic foot ulcers (DFU) cause significant suffering and are often recurring. DFU have three important pathogenic factors, namely, microangiopathy causing local tissue anoxia, neuropathy making the foot prone to injuries from trivial trauma, and local tissue hyperglycaemia favouring infection and delaying the wound healing. DFU have been the leading cause for non-traumatic amputations of part or whole of the limb. Western medicines focus mainly on euglycaemia, antimicrobials, debridement and wound cover with grafts, and off-loading techniques. Advances in euglycaemic control, foot care and footwear, systemic antimicrobial therapy, and overall health care access and delivery, have resulted in an overall decrease in amputations. However, the process of wound care after adequate debridement remains a major cost burden globally, especially in developing nations. This process revolves around two basic concerns regarding control/eradication of local infection and promotion of faster healing in a chronic DFU without recurrence. Wound modulation with various dressings and techniques are often a costly affair. Some aspects of the topical therapy with modern/Western medicines are frequently not addressed. Cost of and compliance to these therapies are important as both the wounds and their treatment are “chronic.” Naturally occurring agents/medications from traditional medicine systems have been used frequently in different cultures and nations, though without adequate clinical base/relevance. Traditional Chinese medicine involves restoring yin-yang balance, regulating the ‘chi’, and promoting local blood circulation. Traditional medicines from India have been emphasizing on ‘naturally’ available products to control wound infection and promote all the aspects of wound healing. There is one more group of chemicals which are not pharmaceutical agents but can create acidic milieu in the wound to satisfy the above-mentioned basic concerns. Various natural and plant derived products (e.g., honey, aloe vera, oils, and calendula) and maggots are also used for wound healing purposes. We believe that patients with a chronic wound are so tired physically, emotionally, and financially that they usually accept native traditional medicine which has the same cultural base, belief, and faith. Many of these products have never been tested in accordance to “evidence-based medicine.” There are usually case reports and experience-based reports about these products. Recently, there have been some trials (in vitro and in vivo) to verify the claims of usage of traditional medicines in management of DFU. Such studies show that these natural products enhance the healing process by controlling infection, stimulating granulation tissue, antimicrobial action, promoting fibroblastic activity and collagen deposition, etc. In this review, we attempt to study and analyse the available literature on results of topical traditional medicines, which are usually advocated in the management of DFU. An integrated and ‘holistic’ approach of both modern and traditional medicine may be more acceptable to the patient, cost effective, and easy to administer and monitor. This may also nevertheless lead to further improvement in quality of life and decrease in the rates of amputations for DFU.
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Affiliation(s)
- Abhijit S Rayate
- Department of Surgery, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Basavraj S Nagoba
- Department of Microbiology, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Sachin S Mumbre
- Department of Community Medicine, Ashwini Rural Medical College, Solapur 413006, India
| | - Hardi B Mavani
- Department of Surgery, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Ajay M Gavkare
- Department of Physiology, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
| | - Advait S Deshpande
- Department of Surgery, Maharashtra Institute of Medical Sciences & Research (Medical College), Latur 413531, India
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Woo K, Dowsett C, Costa B, Ebohon S, Woodmansey EJ, Malone M. Efficacy of topical cadexomer iodine treatment in chronic wounds: Systematic review and meta-analysis of comparative clinical trials. Int Wound J 2021; 18:586-597. [PMID: 33559332 PMCID: PMC8450789 DOI: 10.1111/iwj.13560] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/15/2021] [Accepted: 01/21/2021] [Indexed: 12/24/2022] Open
Abstract
The aim of this study was to summarise the clinical evidence supporting almost 40 years of topical cadexomer iodine (CIOD) use in wound bed preparation by removing barriers to healing such as exudate, slough, bioburden, and infection and allowing chronic wound progression. A systematic review was conducted (Embase/PubMed, November 2020) to identify relevant comparative studies meeting inclusion criteria. Meta‐analyses were performed using a fixed‐effects (I2 < 50%) or random‐effects model (I2 ≥ 50%) depending on statistical heterogeneity. Dichotomous outcomes were reported as relative risk (RR) and continuous outcomes as mean difference (MD), with 95% confidence intervals. In total, 436 publications were identified of which 13 were comparative trials including outcomes of interest. Significant reductions in exudate, pus/debris, slough, bioburden, and infection were reported in chronic wounds treated with CIOD, compared with standard of care (SOC). Meta‐analyses highlighted the positive impact of CIOD on mean wound area reduction (MD = 2.35 cm2, 95% CI = 0.34–4.36, P = .0219) after eight weeks treatment and overall wound healing events compared to SOC; wounds including venous leg ulcers, diabetic foot ulcers, and pressure ulcers treated with CIOD were more than twice as likely to heal than those receiving SOC (RR = 2.30, 95% CI = 1.54–3.45, P < .0001). This meta‐analysis demonstrates the efficacy of CIOD on chronic wounds through removal of barriers to healing. CIOD should be considered in wound bed preparation and treatment protocols.
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Affiliation(s)
- Kevin Woo
- School of Nursing, Queen's University, Kingston, Ontario, Canada
| | | | - Ben Costa
- Smith & Nephew Clinical and Medical Affairs, Kingston upon Hull, UK
| | - Stephen Ebohon
- Smith & Nephew Clinical and Medical Affairs, Kingston upon Hull, UK
| | | | - Matthew Malone
- South West Sydney Limb Preservation and Wound Research, Sydney, Australia.,School of Medicine, Infectious Diseases and Microbiology, Western Sydney University, Australia
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5
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Yasukawa K, Okuno T, Yokomizo T. Eicosanoids in Skin Wound Healing. Int J Mol Sci 2020; 21:ijms21228435. [PMID: 33182690 PMCID: PMC7698125 DOI: 10.3390/ijms21228435] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/06/2020] [Accepted: 11/09/2020] [Indexed: 12/17/2022] Open
Abstract
Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth factors, cytokines, and chemokines are involved in this process and play vital roles in tissue repair. Moreover, recent studies have demonstrated that lipid mediators derived from membrane fatty acids are also involved in the process of wound healing. Among these lipid mediators, we focus on eicosanoids such as prostaglandins, thromboxane, leukotrienes, and specialized pro-resolving mediators, which are produced during wound healing processes and play versatile roles in the process. This review article highlights the roles of eicosanoids on skin wound healing, especially focusing on the biosynthetic pathways and biological functions, i.e., inflammation, proliferation, migration, angiogenesis, remodeling, and scarring.
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Affiliation(s)
- Ken Yasukawa
- Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (K.Y.); (T.Y.)
- Drug Discovery Research Department, Sato Pharmaceutical Co., Ltd., Tokyo 140-0011, Japan
| | - Toshiaki Okuno
- Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (K.Y.); (T.Y.)
- Correspondence: ; Tel.: +81-3-5802-1031
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (K.Y.); (T.Y.)
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6
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Yang Y, Hu H. Application of Superabsorbent Spacer Fabrics as Exuding Wound Dressing. Polymers (Basel) 2018; 10:E210. [PMID: 30966246 PMCID: PMC6415116 DOI: 10.3390/polym10020210] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 02/14/2018] [Accepted: 02/20/2018] [Indexed: 01/22/2023] Open
Abstract
Exuding wound care requires a dressing to quickly absorb exudates and properly manage moisture during the healing process. In this study, the superabsorbent spacer fabrics were designed and fabricated for application in exuding wound dressings. The fabric structure consists of three layers, including two outer hydrophobic layers made of polyester/spandex yarns and one superabsorbent middle layer made of superabsorbent yarns. In order to confirm the performance of these superabsorbent spacer fabrics, their dressing properties were tested and compared with two commercial foam dressings. The results showed that all the superabsorbent spacer fabrics had much faster wetting speeds (less than 2 s) than the foam dressings (6.04 s for Foam A and 63.69 s for Foam B). The absorbency of the superabsorbent spacer fabrics was at least twice higher than that of the foam dressings. The air permeability of the superabsorbent spacer fabrics (higher than 15 mL/s/cm² at 100 Pa) was much higher than that of the foam dressings which had a too low permeability to be measured by the testing device. In addition, the water vapor permeability, thermal insulation, and conformability of superabsorbent spacer fabrics were comparable to foam dressings. The study indicates that the superabsorbent spacer fabrics are suitable for exuding wound dressing applications.
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Affiliation(s)
- Yadie Yang
- Institute of Textiles and Clothing, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
| | - Hong Hu
- Institute of Textiles and Clothing, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
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7
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Green Synthesis of Silver Nanoparticles Using Arachis hypogaea (Ground Nut) Root Extract for Antibacterial and Clinical Applications. J CLUST SCI 2016. [DOI: 10.1007/s10876-016-1084-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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8
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Scientific and Clinical Abstracts From the WOCN® Society's 47th Annual Conference. J Wound Ostomy Continence Nurs 2015; 42 Suppl 3S:S1-S74. [DOI: 10.1097/won.0000000000000148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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9
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To Evaluate Antimicrobial Properties of Platelet Rich Plasma and Source of Colonization in Pressure Ulcers in Spinal Injury Patients. ACTA ACUST UNITED AC 2015. [DOI: 10.1155/2015/749585] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background. Exposure of pressure ulcers (PrUs), particularly to urine and feces, leads to increased colonization of wounds. The aim of the present study was to evaluate the source of microbial colonization and antimicrobial properties of autologous platelet rich plasma (PRP) in controlling it in PrUs. Methods. Twenty-five patients of spinal cord injury (SCI) with at least two PrUs were taken for the study. Local application of autologous PRP on one PrU (case) was compared with saline dressing on the other PrU (control). Urine cultures, urethral meatus, PrUs, and perineal swabs were taken at weekly interval for five weeks. Result. Colonization rate of PrUs (case) decreased from 92% at enrollment to 24% at the 5th week but did not significantly decrease in PrUs (control) from enrollment (84%) to the 5th week (76%). Association between PrU (case) and perineal cultures was observed for Staphylococcus aureus at enrollment 41% (χ2=6.76, P<0.01) and at the 2nd week 47% (χ2=5.83, P<0.05). 47% association between PrU (control) and perineal cultures at enrollment (χ2=4.11, P<0.05) and 29% association at the 2nd week (χ2=8.41, P<0.01) were observed for Staphylococcus aureus. There was association between bacteria present in perineum/urine and those colonizing PrUs. Conclusion. There is a significant association between PrUs colonization and bacteria present in local environment (urine and feces). Local application of autologous PRP changes the “biological milieu” of the PrUs through its antimicrobial properties leading to reduction in bacterial colonization.
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Sesto Cabral ME, Ramos AN, Macedo AJ, Trentin DS, Treter J, Manzo RH, Valdez JC. Formulation and quality control of semi-solid containing harmless bacteria by-products: chronic wounds pro-healing activity. Pharm Dev Technol 2014; 20:911-918. [DOI: 10.3109/10837450.2014.938858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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11
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Liu M, Saeki K, Matsunobu T, Okuno T, Koga T, Sugimoto Y, Yokoyama C, Nakamizo S, Kabashima K, Narumiya S, Shimizu T, Yokomizo T. 12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor. ACTA ACUST UNITED AC 2014; 211:1063-78. [PMID: 24821912 PMCID: PMC4042643 DOI: 10.1084/jem.20132063] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Endogenous 12-HHT, or a synthetic BLT2 agonist promotes epidermal wound closure by stimulating BLT2 on keratinocytes, inducing TNF and MMP production. Leukotriene B4 (LTB4) receptor type 2 (BLT2) is a G protein–coupled receptor (GPCR) for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4. Despite the well-defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive. As mouse BLT2 is highly expressed in epidermal keratinocytes, we investigated the role of the 12-HHT/BLT2 axis in skin wound healing processes. 12-HHT accumulated in the wound fluid in mice, and BLT2-deficient mice exhibited impaired re-epithelialization and delayed wound closure after skin punching. Aspirin administration reduced 12-HHT production and resulted in delayed wound closure in wild-type mice, which was abrogated in BLT2-deficient mice. In vitro scratch assay using primary keratinocytes and a keratinocyte cell line also showed that the 12-HHT/BLT2 axis accelerated wound closure through the production of tumor necrosis factor α (TNF) and matrix metalloproteinases (MMPs). A synthetic BLT2 agonist accelerated wound closure in cultured cells as well as in C57BL/6J and diabetic mice. These results identify a novel mechanism underlying the action of the 12-HHT/BLT2 axis in epidermal keratinocytes and accordingly suggest the use of BLT2 agonists as therapeutic agents to accelerate wound healing, particularly for intractable wounds, such as diabetic ulcers.
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Affiliation(s)
- Min Liu
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuko Saeki
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan
| | - Takehiko Matsunobu
- Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan
| | - Toshiaki Okuno
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan
| | - Tomoaki Koga
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan
| | - Yukihiko Sugimoto
- Department of Pharmaceutical Biochemistry, Kumamoto University, Kumamoto 862-0973, Japan
| | - Chieko Yokoyama
- Department of Metabolism and Atherosclerosis, Osaka University, Osaka 565-0871, Japan
| | - Satoshi Nakamizo
- Department of Dermatology and Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan
| | - Kenji Kabashima
- Department of Dermatology and Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan
| | - Shuh Narumiya
- Department of Dermatology and Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan
| | - Takao Shimizu
- Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo 162-0052, Japan
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan
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12
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Kirkup BC. Culture-independence for surveillance and epidemiology. Pathogens 2013; 2:556-70. [PMID: 25437208 PMCID: PMC4235693 DOI: 10.3390/pathogens2030556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 09/03/2013] [Accepted: 09/05/2013] [Indexed: 12/27/2022] Open
Abstract
Culture-independent methods in microbiology (quantitative PCR (qPCR), sequencing, microarrays, direct from sample matrix assisted laser desorption/ionization time of flight mass spectroscopy (MALDI-TOF MS), etc.) are disruptive technology. Rather than providing the same results as culture-based methods more quickly, more cheaply or with improved accuracy, they reveal an unexpected diversity of microbes and illuminate dark corners of undiagnosed disease. At times, they overturn existing definitions of presumably well-understood infections, generating new requirements for clinical diagnosis, surveillance and epidemiology. However, current diagnostic microbiology, infection control and epidemiology rest principally on culture methods elegantly optimized by clinical laboratorians. The clinical significance is interwoven; the new methods are out of context, difficult to interpret and impossible to act upon. Culture-independent diagnostics and surveillance methods will not be deployed unless the reported results can be used to select specific therapeutics or infection control measures. To cut the knots surrounding the adoption of culture-independent methods in medical microbiology, culture-dependent methods should be supported by consistent culture-independent methods providing the microbial context. This will temper existing biases and motivate appropriate scrutiny of the older methods and results.
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Affiliation(s)
- Benjamin C Kirkup
- Department of Wound Infections, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
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13
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Kuffler DP. Platelet-rich plasma and the elimination of neuropathic pain. Mol Neurobiol 2013; 48:315-32. [PMID: 23832571 DOI: 10.1007/s12035-013-8494-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 06/16/2013] [Indexed: 12/12/2022]
Abstract
Peripheral neuropathic pain typically results from trauma-induced nociceptive neuron hyperexcitability and their spontaneous ectopic activity. This pain persists until the trauma-induced cascade of events runs its full course, which results in complete tissue repair, including the nociceptive neurons recovering their normal biophysical properties, ceasing to be hyperexcitable, and stopping having spontaneous electrical activity. However, if a wound undergoes no, insufficient, or too much inflammation, or if a wound becomes stuck in an inflammatory state, chronic neuropathic pain persists. Although various drugs and techniques provide temporary relief from chronic neuropathic pain, many have serious side effects, are not effective, none promotes the completion of the wound healing process, and none provides permanent pain relief. This paper examines the hypothesis that chronic neuropathic pain can be permanently eliminated by applying platelet-rich plasma to the site at which the pain originates, thereby triggering the complete cascade of events involved in normal wound repair. Many published papers claim that the clinical application of platelet-rich plasma to painful sites, such as muscle injuries and joints, or to the ends of nerves evoking chronic neuropathic pain, a process often referred to as prolotherapy, eliminates pain initiated at such sites. However, there is no published explanation of a possible mechanism/s by which platelet-rich plasma may accomplish this effect. This paper discusses the normal physiological cascade of trauma-induced events that lead to chronic neuropathic pain and its eventual elimination, techniques being studied to reduce or eliminate neuropathic pain, and how the application of platelet-rich plasma may lead to the permanent elimination of neuropathic pain. It concludes that platelet-rich plasma eliminates neuropathic pain primarily by platelet- and stem cell-released factors initiating the complex cascade of wound healing events, starting with the induction of enhanced inflammation and its complete resolution, followed by all the subsequent steps of tissue remodeling, wound repair and axon regeneration that result in the elimination of neuropathic pain, and also by some of these same factors acting directly on neurons to promote axon regeneration thereby eliminating neuropathic pain.
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Affiliation(s)
- Damien P Kuffler
- Institute of Neurobiology, University of Puerto Rico, 201 Blvd. del Valle, San Juan, PR, 00901, USA,
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14
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Drago L, Bortolin M, Vassena C, Taschieri S, Del Fabbro M. Antimicrobial activity of pure platelet-rich plasma against microorganisms isolated from oral cavity. BMC Microbiol 2013; 13:47. [PMID: 23442413 PMCID: PMC3599521 DOI: 10.1186/1471-2180-13-47] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 02/20/2013] [Indexed: 02/06/2023] Open
Abstract
Background Autologous platelet concentrates (PCs) have been extensively used in a variety of medical fields to promote soft and hard tissue regeneration. The significance behind their use lies in the abundance of growth factors in platelets α-granules that promotes wound healing. In addition, antibacterial properties of PCs against various bacteria have been recently pointed out. In this study, the antimicrobial effect of pure platelet-rich plasma (P-PRP) was evaluated against oral cavity microorganisms such as Enterococcus faecalis, Candida albicans, Streptococcus agalactiae, Streptococcus oralis and Pseudomonas aeruginosa. Blood samples were obtained from 17 patients who underwent oral surgery procedures involving the use of P-PRP. The antibacterial activity of P-PRP, evaluated as the minimum inhibitory concentration (MIC), was determined through the microdilution twofold serial method. Results P-PRP inhibited the growth of Enterococcus faecalis, Candida albicans, Streptococcus agalactiae and Streptococcus oralis, but not of Pseudomonas aeruginosa strains. Conclusions P-PRP is a potentially useful substance in the fight against postoperative infections. This might represent a valuable property in adjunct to the enhancement of tissue regeneration.
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Affiliation(s)
- Lorenzo Drago
- Laboratory of Clinical Chemistry and Microbiology, I,R,C,C,S, Galeazzi Orthopaedic Institute, Via R, Galeazzi 4, Milan, 20161, Italy.
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Singh MR, Saraf S, Vyas A, Jain V, Singh D. Innovative approaches in wound healing: trajectory and advances. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2013; 41:202-12. [PMID: 23316788 DOI: 10.3109/21691401.2012.716065] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Wound is one of the oldest suffering associated with the mankind and its history is as old as humanity. Advances in the field of medical sciences created a pile of knowledge and paved the path for the development of a separate branch specifically devoted for wound healing. The understanding and treatment strategies for wound healing have gone through a great revolution. This article reviews all the aspects of wound healing including the pathway, types and recent advances made in the wound care management in particular moist wound dressings using natural polymers, skin grafts, debridement, growth factor and drug delivery.
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Affiliation(s)
- Manju Rawat Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G.), India
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Singh MR, Saraf S, Vyas A, Jain V, Singh D. Innovative approaches in wound healing: trajectory and advances. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2013. [DOI: 10.3109/10731199.2012.716065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Jain R, Agarwal A, Kierski PR, Schurr MJ, Murphy CJ, McAnulty JF, Abbott NL. The use of native chemical functional groups presented by wound beds for the covalent attachment of polymeric microcarriers of bioactive factors. Biomaterials 2013; 34:340-52. [PMID: 23088838 PMCID: PMC3651840 DOI: 10.1016/j.biomaterials.2012.09.055] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 09/23/2012] [Indexed: 12/19/2022]
Abstract
The development of versatile methods that provide spatial and temporal control over the presentation of physical and biochemical cues on wound beds can lead to new therapeutic approaches that expedite wound healing by favorably influencing cellular behaviors. Toward that goal, we report that native chemical functional groups presented by wound beds can be utilized for direct covalent attachment of polymeric microbeads. Specifically, we demonstrated the covalent attachment of maleimide-functionalized and catechol-functionalized microbeads, made of either polystyrene (non-degradable) or poly(lactic-co-glycolic acid) ((PLGA), degradable), to sulfhydryl and amine groups present on porcine dermis used here as an ex vivo model wound bed. A pronounced increase (10-70 fold) in the density and persistence of the covalently reactive microbeads was observed relative to microbeads that adsorb via non-covalent interactions. Complementary characterization of the surface chemistry of the ex vivo wound beds using Raman microspectroscopy provides support for our conclusion that the increased adherence of the maleimide-functionalized beads results from their covalent bond formation with sulfhydryl groups on the wound bed. The attachment of maleimide-functionalized microbeads to wounds created in live wild-type and diabetic mice led to observations of differential immobilization of microbeads on them and were consistent with anticipated differences in the presentation of sulfhydryl groups on the two different wound types. Finally, the incorporation of maleimide-functionalized microbeads in wounds created in wild-type mice did not impair the rate of wound closure relative to an untreated wound. Overall, the results presented in this paper enable a general and facile approach to the engineering of wound beds in which microbeads are covalently immobilized to wound beds. Such immobilized microbeads could be used in future studies to release bioactive factors (e.g., antimicrobial agents or growth factors) and/or introduce topographical cues that promote cell behaviors underlying healing and wound closure.
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Affiliation(s)
- Rishabh Jain
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison
| | - Ankit Agarwal
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison
| | - Patricia R. Kierski
- Department of Surgery, School of Veterinary Medicine, University of Wisconsin-Madison
| | - Michael J. Schurr
- Department of Surgery, School of Medicine and Public Health, University of Colorado-Denver
| | - Christopher J. Murphy
- Department of Ophthalmology & Vision Science, School of Medicine and the Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis
| | - Jonathan F. McAnulty
- Department of Surgery, School of Veterinary Medicine, University of Wisconsin-Madison
| | - Nicholas L. Abbott
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison
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Abstract
Wound bed preparation has been performed for over two decades, and the concept is well accepted. The ‘TIME’ acronym, consisting of tissue debridement, infection or inflammation, moisture balance and edge effect, has assisted clinicians systematically in wound assessment and management. While the focus has usually been concentrated around the wound, the evolving concept of wound bed preparation promotes the treatment of the patient as a whole. This article discusses wound bed preparation and its clinical management components along with the principles of advanced wound care management at the present time. Management of tissue necrosis can be tailored according to the wound and local expertise. It ranges from simple to modern techniques like wet to dry dressing, enzymatic, biological and surgical debridement. Restoration of the bacterial balance is also an important element in managing chronic wounds that are critically colonized. Achieving a balance moist wound will hasten healing and correct biochemical imbalance by removing the excessive enzymes and growth factors. This can be achieved will multitude of dressing materials. The negative pressure wound therapy being one of the great breakthroughs. The progress and understanding on scientific basis of the wound bed preparation over the last two decades are discussed further in this article in the clinical perspectives.
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Affiliation(s)
- A S Halim
- Department of Reconstructive Sciences, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
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Snyder RJ, Cullen B, Nisbet LT. An audit to assess the perspectives of U.S. wound care specialists regarding the importance of proteases in wound healing and wound assessment. Int Wound J 2012; 10:653-60. [PMID: 22846380 DOI: 10.1111/j.1742-481x.2012.01040.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Chronic wounds represent an aberrant biochemistry that creates a toxic proteolytic milieu which can be detrimental to the healing process. Rebalancing the wound microenvironment and addressing elevated protease activity (EPA) could therefore help facilitate healing. To understand how clinicians currently diagnose and manage excessive proteolytic activity, 183 survey responses from US wound specialists were collated and analysed to find out their perceptions on the role of proteases. The majority of respondents (>98%) believed proteases were important in wound healing and that a point-of-care (POC) protease test could be useful. This study yielded a low response rate (7.1%, n = 183); however, there were adequate data to draw significant conclusions. Specialists perceived that fibrin, slough, granulation tissue and rolled wound edges could indicate EPA. About 43% of respondents, however, failed to give a correct response when asked to review photographs to determine if excessive protease activity was present, and the perceived visual signs for EPA did not correlate with the wounds that had EPA; no statistical differences between professions were observed. Respondents chose debridement, wound cleansing and advanced therapies as important in reducing excessive protease activity. It was concluded that specialists have a need for POC diagnostic tests. On the basis of the responses to wound photos, it was determined that there were no visual cues clinicians could use in determining excessive protease activity. Additional research is recommended to evaluate the efficacy of a POC diagnostic test for protease activity and the treatments and therapies applied when EPA is found.
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Affiliation(s)
| | - Breda Cullen
- Systagenix Wound Management, Quincy, MA, USABarry University SPM, Miami Shores, FL, USASystagenix Wound Management, Gargrave, UKSystagenix Wound Management, Airebank Mill, Gargrave, UK
| | - Lorraine T Nisbet
- Systagenix Wound Management, Quincy, MA, USABarry University SPM, Miami Shores, FL, USASystagenix Wound Management, Gargrave, UKSystagenix Wound Management, Airebank Mill, Gargrave, UK
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Burnouf T, Chou ML, Wu YW, Su CY, Lee LW. Antimicrobial activity of platelet (PLT)-poor plasma, PLT-rich plasma, PLT gel, and solvent/detergent-treated PLT lysate biomaterials against wound bacteria. Transfusion 2012; 53:138-46. [PMID: 22563709 DOI: 10.1111/j.1537-2995.2012.03668.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Platelet (PLT) gels exhibit antimicrobial activity useful for wound healing. The nature of the antibacterial component(s) is unknown. STUDY DESIGN AND METHODS PLT-poor plasma (PPP), PLT-rich plasma (PRP), PLT gel (PG), and solvent/detergent-treated PLT lysate (S/D-PL) from two donors were evaluated either native or after complement heat inactivation. Materials were spiked at a 10% ratio (vol/vol) with approximately 10(7-8) colony-forming units/mL with four Gram-positive and four Gram-negative bacteria of the wound flora. Bacterial count was determined by plate assays at time of spiking and after 3 and 48 hours at 31°C. Bacteria growth inhibition tests were also performed. RESULTS There was no viable Escherichia coli colony for 48 hours after spiking to the plasma and PLT materials from both donors, corresponding to greater than 7.51 to greater than 9.05 log inactivation. Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus were inactivated (approx. 4.7, 7, and 2 log, respectively) 3 hours after spiking to PRP, PPP, or S/D-PL from the first donor but less (1.1, 4.6, and 0.2 log, respectively) in PG, before a regrowth at 48 hours in all materials. Similar data were obtained with the second donor. No plasma and PLT material had antimicrobial activity against Enterobacter cloacae, Bacillus cereus, Bacillus subtilis, and Staphylococcus epidermidis. Complement-inactivated samples had no antimicrobial activity. CONCLUSION Plasma complement is mostly responsible for the activity of plasma and PLT biomaterials against E. coli, P. aeruginosa, K. pneumoniae, and S. aureus. Activation of the coagulation to prepare PG may reduce antimicrobial activity. These findings may help optimize the control of wound infections by blood biomaterials.
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Affiliation(s)
- Thierry Burnouf
- College of Oral Medicine and the Department of Microbiology and Immunology, Taipei Medical University, Taipei, Taiwan
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21
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Spear M. Infected? Or not? Plast Surg Nurs 2011; 31:174-175. [PMID: 22157609 DOI: 10.1097/psn.0b013e31823c445c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
The criteria described earlier should be considered when the classic signs of wound infection do not appear. These criteria should also be considered in the presence of delayed wound healing as delayed wound healing should produce a high suspicion of an existing wound infection.The importance of the early recognition and suspicion of wound infection should not be underestimated because of the high economic burden of prolonged treatment and human suffering.The challenge to the practitioner lies in possessing knowledge and ability to recognize the state of a wound in relation to the bacterial continuum and intervene appropriately.
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Affiliation(s)
- Marcia Spear
- Department of Plastic Surgery at Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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23
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VAALAMO M, WECKROTH M, PUOLAKKAINEN P, KERE J, SAARINEN P, LAUHARANTA J, SAARIALHO-KERE U. Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 2008. [DOI: 10.1046/j.1365-2133.1996.d01-932.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Bell A, Hart J. Evaluation of two absorbent silver dressings in a porcine partial-thickness excisional wound model. J Wound Care 2007; 16:445-8, 450-3. [DOI: 10.12968/jowc.2007.16.10.27911] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- A Bell
- Institute for Molecular and Cellular Biology, University of Leeds, West Yorkshire, LS2 9JT, UK
| | - J Hart
- Cica Biomedical Ltd, PO Box 146, Knaresborough, North Yorkshire HG5 9WB, UK
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25
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Abstract
In the last few years, considerable progress has been made in the treatment of chronic ulcers, thanks to new therapy methods. Wound bed preparation is a modern approach for the removal of local barriers to healing by optimising debridement, reduction of bioburden and exudate management through the TIME principles, which have been introduced by the International Advisory Board on Wound Bed Preparation. However, this protocol does not evaluate the state of the repair process and therefore does not suggest the ideal therapeutic choice for each single patient. The revised TIME-H concept considers also the supposed healing time, H, and gives a score that correlates the wound condition with the incidental concomitance with medical pathologies related to the therapeutic measures, thus guiding the clinician towards a practical and systematic approach in the treatment. By applying this scheme to our situation, the average healing time was considerably reduced. The formulation of the new protocol TIME-H for a critical assessment of treatment scheme, which also includes the general conditions of the patient, represents a more rational and adequate approach for an accurate prognosis and therefore for a more suitable therapeutic choice in the treatment of difficult wounds.
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Affiliation(s)
- Claudio Ligresti
- Reparto di Chirurgia Plastica, Department of Plastic Surgery, Centre of Reference for Serious Wound Treatment, Cardinal Massaia Hospital of A.S.L. 19, Asti, Italy.
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26
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Abstract
This paper explores the nature of evidence and how it has evolved in recent years, and sets out a process for assembling and assessing the evidence to support wound bed preparation as an effective method of managing chronic wounds
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Nigam Y, Bexfield A, Thomas S, Ratcliffe NA. Maggot therapy: the science and implication for CAM part II-maggots combat infection. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2006; 3:303-8. [PMID: 16951714 PMCID: PMC1513154 DOI: 10.1093/ecam/nel022] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2005] [Accepted: 03/23/2006] [Indexed: 12/30/2022]
Abstract
Maggot therapy employs the use of freshly emerged, sterile larvae of the common green-bottle fly, Phaenicia (Lucilia) sericata, and is a form of artificially induced myiasis in a controlled clinical situation. Maggot therapy has the following three core beneficial effects on a wound: debridement, disinfection and enhanced healing. In part II of this review article, we discuss clinical infections and the evidence supporting the potent antibacterial action of maggot secretions. Enhancement of wound healing by maggots is discussed along with the future of this highly successful, often controversial, alternative treatment.
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Affiliation(s)
- Yamni Nigam
- School of Health Science, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK,
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28
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29
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Menke NB, Diegelmann RF. Biochemical Pathways of Wound Healing: Implications for Development of Disease‐Specific Diagnostics. Adv Clin Chem 2006; 41:167-187. [DOI: 10.1016/s0065-2423(05)41005-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Penhallow K. A review of studies that examine the impact of infection on the normal wound-healing process. J Wound Care 2005; 14:123-6. [PMID: 15779643 DOI: 10.12968/jowc.2005.14.3.26747] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Wound infection disrupts the normal healing process, although to what extent is not proven. This review explores controversies in the literature surrounding the bacterial load of the chronic wound and its impact, if any, on this process.
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Affiliation(s)
- K Penhallow
- Worthing and Southlands Hospitals NHS Trust, UK.
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31
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Abstract
Managing chronic wounds has progressed from merely assessing the wound to understanding the underlying cellular abnormalities and associated clinical problems. The concept of wound bed preparation offers a systematic approach to removing barriers to healing such as tissue (non-viable), infection/inflammation, moisture (imbalance) and edge (non-advancing or undermining). The principles of wound bed preparation as outlined in the tissue, infection, moisture, edge (TIME) table are explained in this article, with examples and recommended treatment interventions. The TIME table is recommended for use at the bedside when assessing patients with wounds.
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32
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Viennet C, Armbruster V, Gabiot AC, Gharbi T, Bride J, Humbert P. Comparing the contractile properties of human fibroblasts in leg ulcers with normal fibroblasts. J Wound Care 2004; 13:358-61. [PMID: 15517743 DOI: 10.12968/jowc.2004.13.9.26706] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The tissue contraction phenomenon associated with wound healing is of prime importance for wound closure. Contractile properties of human fibroblasts from chronic venous leg ulcers were compared with those of normal fibroblasts using in vitro models. METHOD Biopsies were taken from the uninvolved skin of the thigh, the epithelialised ulcer edge and the non-epithelialised ulcer centre in four patients (average age: 78 years). Fibroblasts were obtained by an explant technique and expanded in vitro in Dulbecco's Modified Eagle's Medium supplemented with 10% foetal calf serum and used for the assays at their fourth passage. Intracellular alpha-smooth muscle actin expression (alphaSM-actin) was studied by immunofluorescence labelling of cells cultured in monolayer. Contractile properties were evaluated using three-dimensional collagen lattices. RESULTS Fibroblasts from the ulcer centre were the richest cells in actin filaments. Both populations of venous ulcer fibroblasts contracted more rapidly and to a greater extent than normal fibroblasts. The peak contractile forces developed by fibroblasts from the ulcer centre and the ulcer edge were 30% and 18% greater than normal fibroblasts respectively. CONCLUSION Some functions of fibroblasts, in particular the generation of contractile forces and the formation of cytoplasmic actin filaments, seem not to be affected in chronic venous ulcers. DECLARATION OF INTEREST This study was supported by the Fondation Coloplast pour la Qualite de la Vie of France.
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Affiliation(s)
- C Viennet
- I Engineering and Cutaneous Biology Laboratory, School of Medicine and Pharmacy, Besançon, France
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33
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Abstract
Although it is well recognized that pressure-induced ischemia initiates the formation of pressure ulcers, the many complex mechanisms responsible for the pathogenesis of these ulcers remain poorly understood. It has been reported that chronic ulcers contain an elevated level of proteolytic enzymes, especially neutrophil-derived matrix metalloproteinase-8 and elastase. This evidence suggests that neutrophils are a major component in the pathogenesis of chronic pressure ulcers. Therefore, this study characterized the cellular components of chronic pressure ulcers. Three-millimeter biopsies (6 mm deep) from granulation tissue in pressure ulcers were obtained from 11 patients. A total of 14 biopsies were obtained from these 11 patients for analysis. A portion of each specimen was fixed in formalin for routine histology. Other portions of biopsies were frozen for analysis of myeloperoxidase activity. In addition, cells on the surfaces of the ulcers were collected by lavage for histologic characterization. Routine histologic analysis of all 14 biopsies of the pressure ulcers showed regions near the surface of each that contained dense neutrophil infiltration associated with edema and apparent marked matrix dissociation. In the deeper regions there was an increased density of blood vessels, and many contained rounded endothelial cells surrounded by migrating neutrophils. Cells collected by lavage from the ulcer surface were prepared by Cytospin and found to be greater than 95% neutrophils with occasional large macrophages actively phagocytosing depleted neutrophils. In addition, there was a significant correlation of myeloperoxidase activity with actual neutrophil counts in the ulcer biopsies further confirming the dense presence of neutrophils. These studies directly show that there is extensive neutrophil infiltration in chronic pressure ulcer granulation tissue. Furthermore, the persistence of neutrophils and their destructive enzymes appears responsible for the extensive matrix dissociation and thus contributes to the chronicity of these ulcers.
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Affiliation(s)
- Robert F Diegelmann
- Department of Biochemistry, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia 23298-0614, USA.
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34
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Kan C, Abe M, Yamanaka M, Ishikawa O. Hypoxia-induced increase of matrix metalloproteinase-1 synthesis is not restored by reoxygenation in a three-dimensional culture of human dermal fibroblasts. J Dermatol Sci 2003; 32:75-82. [PMID: 12788533 DOI: 10.1016/s0923-1811(03)00032-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Delayed wound healing is multi-factorial. Although ischemic change is considered to be crucial, little is known about the effects of hypoxia or reoxygenation on the connective tissue metabolism by human dermal fibroblasts. OBJECTIVE The aim of this study is to determine whether or not hypoxia (2% O(2)) or reoxygenation (20% O(2)) affects mRNA expression and production of matrix metalloproteinase-1 (MMP-1), type I collagen, tissue inhibitors of metalloproteinase-1 (TIMP-1), and transforming growth factor-beta1 (TGF-beta1) by human dermal fibroblasts in a three-dimensional culture. METHODS We introduced the three-dimensional culture of human dermal fibroblasts with experimental wound. After wounding, cells were incubated under hypoxic (2%) or normoxic (20%) condition, and harvested at 24, 36, 48, and 72 h (n=8). In the reoxygenation study (n=4), cells were first exposed to a hypoxic condition for 72 h and further incubated under a normoxic condition for 72 h. RESULTS The relative ratio (hypoxia/normoxia) of MMP-1 mRNA expressions were significantly elevated at 36 and 48 h compared with those at 12 h (P<0.05). The relative ratio of proMMP-1 was also significantly increased at 48 and 72 h compared with that at 12 h (P<0.001 and P<0.05, respectively). There were no significant changes in mRNA and protein levels of type I collagen, TGF-beta1, and TIMP-1. In a reoxygenic condition, 72 h reoxygenation after 72 h hypoxia, the hypoxia-induced alterations of MMP-1 and carboxyterminal propeptide of type I procollagen (PIP) were not restored. CONCLUSION Our results indicate that hypoxia may be responsible for delayed wound healing by inducing an increase of MMP-1 synthesis.
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Affiliation(s)
- Chie Kan
- Department of Dermatology, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan.
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Cheng ML, Ho HY, Huang YW, Lu FJ, Chiu DTY. Humic acid induces oxidative DNA damage, growth retardation, and apoptosis in human primary fibroblasts. Exp Biol Med (Maywood) 2003; 228:413-23. [PMID: 12671186 DOI: 10.1177/153537020322800412] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Humic acid (HA) has been implicated as an etiological factor of Blackfoot disease endemic in the southwest coast of Taiwan. Dysfunction of endothelial cells and vasculopathy have been proposed to explain the onset of ulcerous changes at extremities. However, little is known about the effect of HA on activities of cells in these nonhealing wounds. In the present study, we demonstrate that HA adversely affects the growth properties of fibroblasts, one of the key players in wound repair. HA treatment caused growth arrest and apoptosis in human foreskin fibroblasts (HFF). This was accompanied by a significant increase in the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in cellular DNA. The increased fluorescence in dichlorofluorescin (H2DCF)-stained and HA-treated cells suggests the involvement of reactive oxygen species (ROS) in HA-induced biological effects. Conversely, vitamin E pretreatment, which significantly reduced the 8-OHdG formation in HA-treated cells, alleviated the growth-inhibitory and apoptosis-inducing effects of HA. These results indicate that HA initiates oxidative damages to fibroblasts, and leads to their dwindling growth potential and survival. The present study suggests that HA-induced growth retardation and apoptosis of fibroblasts may play a role in the pathogenesis of Blackfoot disease.
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Affiliation(s)
- Mei-Ling Cheng
- Graduate Institute of Medical Biotechnology and School of Medical Technology, Chang Gung University, Kwei-san, Tao-yuan, Taiwan
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Schultz GS, Sibbald RG, Falanga V, Ayello EA, Dowsett C, Harding K, Romanelli M, Stacey MC, Teot L, Vanscheidt W. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen 2003; 11 Suppl 1:S1-28. [PMID: 12654015 DOI: 10.1046/j.1524-475x.11.s2.1.x] [Citation(s) in RCA: 734] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The healing process in acute wounds has been extensively studied and the knowledge derived from these studies has often been extrapolated to the care of chronic wounds, on the assumption that nonhealing chronic wounds were simply aberrations of the normal tissue repair process. However, this approach is less than satisfactory, as the chronic wound healing process differs in many important respects from that seen in acute wounds. In chronic wounds, the orderly sequence of events seen in acute wounds becomes disrupted or "stuck" at one or more of the different stages of wound healing. For the normal repair process to resume, the barrier to healing must be identified and removed through application of the correct techniques. It is important, therefore, to understand the molecular events that are involved in the wound healing process in order to select the most appropriate intervention. Wound bed preparation is the management of a wound in order to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. Experts in wound management consider that wound bed preparation is an important concept with significant potential as an educational tool in wound management. This article was developed after a meeting of wound healing experts in June 2002 and is intended to provide an overview of the current status, role, and key elements of wound bed preparation. Readers will be able to examine the following issues; the current status of wound bed preparation; an analysis of the acute and chronic wound environments; how wound healing can take place in these environments; the role of wound bed preparation in the clinic; the clinical and cellular components of the wound bed preparation concept; a detailed analysis of the components of wound bed preparation.
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Affiliation(s)
- Gregory S Schultz
- Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida, USA
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Lauer G, Sollberg S, Cole M, Krieg T, Eming SA. Generation of a novel proteolysis resistant vascular endothelial growth factor165 variant by a site-directed mutation at the plasmin sensitive cleavage site. FEBS Lett 2002; 531:309-13. [PMID: 12417332 DOI: 10.1016/s0014-5793(02)03545-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Vascular endothelial growth factor (VEGF) is a potent angiogenic mediator in tissue repair. In non-healing human wounds plasmin cleaves and inactivates VEGF165. In the present study, we generated recombinant VEGF165 mutants resistant to plasmin proteolysis. Substitution of Arg110 with Ala110 or Gln110, and Ala111 with Pro111 yielded plasmin-resistant and biologically active VEGF165 mutants. In addition, substitution of Ala111 with Pro111 resulted in a substantial degree of stabilization when incubated in wound fluid obtained from non-healing wounds. These results suggest that the plasmin cleavage site Arg110/Ala111 and the carboxyl-terminal domain play an important role in the mitogenic activity of VEGF165.
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Affiliation(s)
- Gereon Lauer
- Department of Dermatology, University of Cologne, Cologne, Germany
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38
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Abstract
Many patients are now having minor surgical procedures carried out in the community and those patients who undergo surgery in hospital are likely to be discharged earlier due to increasing pressure on hospital beds. This article discusses the management of surgical wounds healing by both primary and secondary closure, in the community setting. Understanding the complex process of wound healing is essential if nurses are to recognize abnormalities and select appropriate treatments for patients. The stages of wound healing will be discussed in detail, including the patient's presentation. Factors that influence this process within the patient (e.g. age, nutrition, medication and pain) and those at the wound bed (e.g. exudate, tissue type and infection) will be highlighted. Choosing the correct type of surgical wound dressing for the type of wound can contribute to wound healing, patient comfort and the cost-effectiveness of treatment. Factors that need to be taken into consideration when choosing a dressing will be outlined and suggestions made for the type of dressings that would be most appropriate. The importance of accurate and detailed documentation will be highlighted as part of this process.
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Mohan R, Chintala SK, Jung JC, Villar WVL, McCabe F, Russo LA, Lee Y, McCarthy BE, Wollenberg KR, Jester JV, Wang M, Welgus HG, Shipley JM, Senior RM, Fini ME. Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration. J Biol Chem 2002; 277:2065-72. [PMID: 11689563 DOI: 10.1074/jbc.m107611200] [Citation(s) in RCA: 194] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We studied the role of the matrix metalloproteinase gelatinase B (gelB; MMP-9) in epithelial regeneration using the gelB-deficient mouse. We report the novel finding that, in contrast to other MMPs expressed at the front of the advancing epithelial sheet in wounds of cornea, skin, or trachea, gelB acts to inhibit the rate of wound closure. We determined this to be due to control of cell replication, a novel capacity for MMPs not previously described. We also found that gelB delays the inflammatory response. Acceleration of these processes in gelB-deficient mice is correlated with a delay in signal transduction through Smad2, a transcription factor that inhibits cell proliferation, and in accumulation of epithelial-associated interleukin-1alpha, a cytokine that inhibits Smad2 signaling and promotes the inflammatory response. GelB-deficient mice also reveal defects in remodeling of extracellular matrix at the epithelial basement membrane zone, in particular, failure to effectively remove the fibrin(ogen) provisional matrix. We conclude that gelB coordinates and effects multiple events involved in the process of epithelial regeneration.
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Affiliation(s)
- Royce Mohan
- New England Eye Center, Tufts University School of Medicine, and the Tufts Center for Vision Research, Boston, Massachusetts 02111, USA
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Cowin AJ, Hatzirodos N, Holding CA, Dunaiski V, Harries RH, Rayner TE, Fitridge R, Cooter RD, Schultz GS, Belford DA. Effect of healing on the expression of transforming growth factor beta(s) and their receptors in chronic venous leg ulcers. J Invest Dermatol 2001; 117:1282-9. [PMID: 11710945 DOI: 10.1046/j.0022-202x.2001.01501.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The transforming growth factor betas are of major importance in the wound repair process; however, no studies to date have investigated the role of the transforming growth factor beta receptors in chronic venous leg ulcers or what effect healing has on these proteins. To determine whether the transforming growth factor beta peptides and their receptors are expressed in chronic venous wounds, we used immunofluorescent analysis and quantitative competitive reverse transcription polymerase chain reaction to identify the protein and mRNA expression, respectively. Biopsy samples from wounds and normal skin were collected from 12 patients with chronic venous leg ulcers and three patients undergoing reconstructive surgery, respectively. Additionally four of the chronic venous leg ulcer patients were re-biopsied between 2 and 8 wk after the first biopsy when the wounds had entered the healing phase. The tissue excised from the ulcers included the surrounding intact skin, the ulcer edge, and the ulcer base. Immunofluorescent staining for transforming growth factors beta1, beta2, and beta3 was observed within the epidermis of the skin surrounding the chronic venous ulcers and in fibroblasts and inflammatory cells of the dermis, although this staining was not as strong as that seen in normal unwounded skin. Very little staining could be seen within the ulcers for any of the ligands, however. In contrast the transforming growth factor beta type I receptor was observed throughout the ulcers and the normal unwounded skin biopsies, particularly in the basal epidermal cells. No immunofluorescence for the type II transforming growth factor beta receptor was observed in any of the ulcer biopsies investigated, although it was observed throughout the epidermis and in fibroblasts and inflammatory cells in the surrounding skin. Quantitative, competitive reverse transcription polymerase chain reaction was used to analyze mRNA expression for transforming growth factor beta1 and the type II receptor in the nonhealing ulcers and normal unwounded skin biopsies. These studies revealed that transforming growth factor beta1 and transforming growth factor beta receptor II mRNA was expressed in all the chronic nonhealing ulcers albeit at very low levels for the type II receptor. In marked contrast to the staining observed in nonhealing chronic ulcers, positive immunostaining was observed for the transforming growth factor betas and both the type I and type II receptors in healing ulcers. These results suggest that the absence of a viable receptor complex for the transforming growth factor betas in nonhealing chronic venous ulcers may contribute to wound chronicity.
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Affiliation(s)
- A J Cowin
- Cooperative Research Center for Tissue Growth and Repair, Child Health Research Institute, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
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Abe Y, Inagaki K, Fujiwara A, Kuriyama K. Wound healing acceleration of a novel transforming growth factor-beta inducer, SEK-1005. Eur J Pharmacol 2000; 408:213-8. [PMID: 11080528 DOI: 10.1016/s0014-2999(00)00766-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The studies were carried out to elucidate the effect of a novel cyclic peptide, SEK-1005 (C(45)H(70)N(8)O(13)), on wound healing. SEK-1005 (4-10 microg/wound) applied topically significantly accelerated the healing of a full-thickness wound on the dorsal skin of a rat. In a healing-impaired mouse, the peptide (2-10 microg/wound) had more potent activity, exerting an effect comparable to that of basic fibroblast growth factor (FGF). However, SEK-1005 (0.1-100 ng/ml) scarcely promoted the proliferation of cultured fibroblasts (NIH3T3 cells) while basic FGF (0.2-5 ng/ml) showed marked mitogenic activity. SEK-1005 (2-10 microg/wound) significantly increased the topical production of transforming growth factor (TGF)-beta1, a cytokine that is known to accelerate wound healing. This activity was closely correlated with the wound-repairing effect. From the above, SEK-1005 can be considered as a new type of wound healing agent with potent TGF-beta1-inducing activity.
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Affiliation(s)
- Y Abe
- Medical Research Laboratory, Sekisui Chemical Co., LTD., 2-1 Hyakuyama Shimamoto-cho, Mishima-gun, 618-0021, Osaka, Japan.
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Abstract
The application of gene transfer strategies to wound healing is not an obvious use of this technology until one considers the important role of cytokines and growth factors in the normal wound healing response. Several gene transfer strategies have been proposed, from in vitro retroviral-mediated gene transfer with autologous transplantation, to in vivo plasmid based gene transfer as retroviral gene transfer. The limitations of these approaches have been efficiency of gene transfer, transgene expression and biologic response. Adenoviral-mediated gene transfer in wound healing is a relatively new application of this vector. The advantage of the adenovirus as a gene transfer vector lies in its ability to transduce nondividing cells of all types at very high efficiency without integration into the host cell's genome. The disadvantage of adenovirus as a vector is the relatively short duration of transgene expression and the inflammatory response it elicits. In the setting of wound healing brief duration of high levels of transgene may be all that is necessary to favorably influence wound healing. Secondly, as wound healing is fundamentally an inflammatory response, the inflammation elicited by the adenovirus may not be detrimental as long as the transgene is a growth factor with significant vulnerary effects such as platelet-derived growth factor-B. This review summarizes the current state of adenoviral-mediated gene transfer in experimental models of impaired wound healing which have laid the groundwork for proposed phase I clinical trials of adenoviral-mediated gene transfer of platelet-derived growth factor-B in chronic venous leg ulcers and chronic nonhealing diabetic foot ulcers. Adenoviral-mediated gene transfer is a useful tool in the study of the role of specific cytokines and growth factors in normal and impaired wound healing. Adenoviral-mediated gene transfer may hold significant promise for clinical application as a means of efficient growth factor delivery in correcting impaired wound healing.
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Affiliation(s)
- T M Crombleholme
- Children's Institute for Surgical Science, The Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104, USA.
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Yamanaka M, Ishikawa O. Hypoxic conditions decrease the mRNA expression of proalpha1(I) and (III) collagens and increase matrix metalloproteinases-1 of dermal fibroblasts in three-dimensional cultures. J Dermatol Sci 2000; 24:99-104. [PMID: 11064244 DOI: 10.1016/s0923-1811(00)00086-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The effect of hypoxia on the expression of extracellular matrix-related genes by human dermal fibroblasts was investigated using a novel three-dimensional culture supplemented with L-ascorbic acid 2-phosphate. Experiments were performed by placing replicate dishes in either hypoxic (2%) or in normoxic (20%) condition for various periods of time ranging up to 72 h. The mRNA expression levels of proalpha1(I), proalpha1(III) collagens and MMP-1 were analyzed using Northern blotting. Hypoxia transiently increased proalpha1(I) and proalpha1(III) collagen gene expression at 24 h, but a prolonged exposure to hypoxia decreased them. A slight increase in MMP-1 mRNA was observed at 24 h and prolonged exposure for up 72 h resulted in significantly increased expression of MMP-1 gene. Our results suggest that enhanced degradation as well as decreased synthesis of collagens induced by hypoxia may account for the delayed wound healing associated with circulatory disturbances.
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Affiliation(s)
- M Yamanaka
- Department of Dermatology, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, 371-8511, Gunma, Japan.
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Tarlton JF, Bailey AJ, Crawford E, Jones D, Moore K, Harding KD. Prognostic value of markers of collagen remodeling in venous ulcers. Wound Repair Regen 1999; 7:347-55. [PMID: 10564563 DOI: 10.1046/j.1524-475x.1999.00347.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
A 25 patient study was conducted into the relationship between markers of collagen metabolism in venous ulcer exudates and healing status, and their prognostic value in predicting healing performance. Wounds were sampled on at least 5 occasions over 12 months, the frequencies of which were determined by the need for clinic attendance. Specimens were taken from several sites on each ulcer using sterile preweighed filters. Wound margins were traced and sites recorded for each collection. Sample sites were evaluated for severity as improving, static, or deteriorating according to subsequent wound progression. Specimens were analyzed for levels of proenzyme and active forms of matrix metalloproteinases 2 and 9, neutrophil elastase, and type I collagen C propeptide. There was an overall trend of greater expression of all markers with increasing severity of wound site, this being highly significant for pro-matrix metalloproteinase-9 (p = 0.006). For samples collected simultaneously from improving and deteriorating regions of the same wound, paired data analysis showed statistically significant differences for pro-matrix metalloproteinase-9 (p < 0.001), neutrophil elastase (p < 0.005) and activated matrix metalloproteinase-9 (p < 0.05). Taken overall, these data show the potential of markers of collagen biochemistry as predictors of repair in venous ulcers; in particular pro-matrix metalloproteinase-9 and neutrophil elastase were found to be accurate prognostic indicators of subsequent healing.
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Affiliation(s)
- J F Tarlton
- Collagen Research Group, Division of Molecular and Cellular Biology, University of Bristol, United Kingdom.
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Agren MS, Steenfos HH, Dabelsteen S, Hansen JB, Dabelsteen E. Proliferation and mitogenic response to PDGF-BB of fibroblasts isolated from chronic venous leg ulcers is ulcer-age dependent. J Invest Dermatol 1999; 112:463-9. [PMID: 10201530 DOI: 10.1046/j.1523-1747.1999.00549.x] [Citation(s) in RCA: 116] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Several pathophysiologic mechanisms have been proposed to explain slow-healing leg ulcers, but little is known about the growth behavior of cells in these wounds. Platelet-derived growth factor-BB applied topically to chronic wounds has shown beneficial effects, although the effects have been less pronounced than would have been expected based on studies on acute wounds. The objective of this study was to compare fibroblasts in culture obtained from chronic wounds (non-healing chronic venous leg ulcers), acute wounds and normal dermis regarding growth, mitogenic response to platelet-derived growth factor-BB and levels ofplatelet-derived growth factor alpha-receptor and beta-receptor. Fibroblasts were obtained by an explant technique and expanded in vitro using fibroblast growth medium supplemented with 10% fetal bovine serum and used for the assays at their third passage. Growth of chronic wound fibroblasts (n = 8) was significantly (p < 0.05) decreased compared with those from acute wounds (n = 10) and normal dermis (n = 5). Fibroblasts from ulcers older than 3 y grew significantly (p < 0.01) slower than those from ulcers that had been present for less than 3 y. Morphology and size of fibroblasts from the oldest chronic wounds deviated substantially from those of acute wounds and normal dermis, and resembled in vitro aged or senescent fibroblasts. Mitogenic response of chronic wound fibroblasts to human recombinant platelet-derived growth factor-BB was also reduced with ulcer age. No significant differences were found in the amount of either platelet-derived growth factor alpha-receptor or beta-receptor among the three groups. The features decreased growth related to ulcer age, altered morphology, and reduced response to platelet-derived growth factor, indicating that fibroblasts in some chronic wounds have approached or even reached the end of their lifespan (phase III). This might provide one explanation for the non-healing state and therapy resistance to topical platelet-derived growth factor-BB of some venous leg ulcers.
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Affiliation(s)
- M S Agren
- Coloplast Research, Humlebaek, Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark
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Grinnell F, Zhu M, Parks WC. Collagenase-1 complexes with alpha2-macroglobulin in the acute and chronic wound environments. J Invest Dermatol 1998; 110:771-6. [PMID: 9579544 DOI: 10.1046/j.1523-1747.1998.00192.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The purpose of this study was to examine the appearance and activation of collagenase-1 (MMP-1) in the wound environment. We found that MMP-1 accumulates in the fluid phase of the burn wound environment within 2 d of injury and reaches maximal levels by day 4. Two forms of the enzyme were evident; one that corresponded to proMMP-1 and another that corresponded to a group of high molecular mass (approximately 200 kDa and >200 kDa doublet) MMP-1 containing complexes. ProMMP-1 and MMP-1 containing complexes also occurred in wound fluid from venous stasis ulcers, but neither was detected in mastectomy fluid or in plasma. Levels of the proteinase inhibitor alpha2-macroglobulin in burn fluid and chronic ulcer wound fluid were almost as high as in plasma, and the high molecular mass MMP-1 containing complexes in burn fluid appeared to result from binding between alpha2-macroglobulin and activated MMP-1. These observations provide direct evidence that active MMP-1 in the fluid phase of the wound environment becomes complexed to alpha2-macroglobulin.
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Affiliation(s)
- F Grinnell
- Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical School, Dallas 75235, USA
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He Y, Young PK, Grinnell F. Identification of proteinase 3 as the major caseinolytic activity in acute human wound fluid. J Invest Dermatol 1998; 110:67-71. [PMID: 9424090 DOI: 10.1046/j.1523-1747.1998.00075.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Wound fluid contains several proteinases that are important in the repair process. In this study, we analyzed caseinolytic activity in wound fluid obtained from acute (burn) wounds. Caseinolytic activity in wound fluid increased markedly 2 d after injury and appeared on casein zymographs as a series of bands or a smear ranging from 30 to 100 kDa. Most of the enzyme activity was inhibited by the synthetic human neutrophil elastase inhibitor MDL 27,367 but not by the naturally occurring inhibitor of elastase, human secretory leukoproteinase inhibitor. Fractionation of wound fluid indicated that a single enzyme accounted for approximately 80% of the caseinolytic activity. This enzyme degraded the elastase substrate methoxysuccinyl-ala-ala-pro-val-p-nitroanilide at a slow rate. The above findings suggested that the enzyme responsible for caseinolytic activity might be proteinase 3, an elastase-related enzyme whose physiologic functions are poorly understood. Consistent with the above possibility, we found that monoclonal antibodies against proteinase 3 removed caseinolytic activity from wound fluid, and that purified proteinase 3 had a similar caseinolytic profile and inhibitor sensitivity to burn fluid.
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Affiliation(s)
- Y He
- Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center, Dallas 75235, USA
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Wlaschek M, Peus D, Achterberg V, Meyer-Ingold W, Scharffetter-Kochanek K. Protease inhibitors protect growth factor activity in chronic wounds. Br J Dermatol 1997; 137:646. [PMID: 9390348 DOI: 10.1111/j.1365-2133.1997.tb03804.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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VAALAMO M, WECKROTH M, PUOLAKKAINEN P, KERE J, SAARINEN P, LAUHARANTA J, SAARIALHO-KERE U. Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 1996. [DOI: 10.1111/j.1365-2133.1996.tb03607.x] [Citation(s) in RCA: 116] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Xia Y, Gil SG, Carter WG. Anchorage mediated by integrin alpha6beta4 to laminin 5 (epiligrin) regulates tyrosine phosphorylation of a membrane-associated 80-kD protein. J Cell Biol 1996; 132:727-40. [PMID: 8647901 PMCID: PMC2199869 DOI: 10.1083/jcb.132.4.727] [Citation(s) in RCA: 104] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Detachment of basal keratinocytes from basement membrane signals a differentiation cascade. Two integrin receptors alpha6beta4 and alpha3beta1 mediate adhesion to laminin 5 (epiligrin), a major extracellular matrix protein in the basement membrane of epidermis. By establishing a low temperature adhesion system at 4 degrees C, we were able to examine the exclusive role of alpha6beta4 in adhesion of human foreskin keratinocyte (HFK) and the colon carcinoma cell LS123. We identified a novel 80-kD membrane-associated protein (p80) that is tyrosine phosphorylated in response to dissociation of alpha6beta4 from laminin 5. The specificity of p80 phosphorylation for laminin 5 and alpha6beta4 was illustrated by the lack of regulation of p80 phosphorylation on collagen, fibronectin, or poly-L-lysine surfaces. We showed that blocking of alpha3beta1 function using inhibitory mAbs, low temperature, or cytochalasin D diminished tyrosine phosphorylation of focal adhesion kinase but not p80 phosphorylation. Therefore, under our assay conditions, p80 phosphorylation is regulated by alpha6beta4, while motility via alpha3beta1 causes phosphorylation of focal adhesion kinase. Consistent with a linkage between p80 dephosphorylation and alpha6beta4 anchorage to laminin 5, we found that phosphatase inhibitor sodium vanadate, which blocked the p80 dephosphorylation, prevented the alpha6beta4-dependent cell anchorage to laminin 5 at 4degreesC. In contrast, adhesion at 37 degrees C via alpha3beta1 was unaffected. Furthermore, by in vitro kinase assay, we identified a kinase activity for p80 phosphorylation in suspended HFKs but not in attached cells. The kinase activity, alpha6beta4, and its associated adhesion structure stable anchoring contacts were all cofractionated in the Triton-insoluble cell fraction that lacks alpha3beta1. Thus, regulation of p80 phosphorylation, through the activities of p80 kinase and phosphatase, correlates with alpha6beta4-SAC anchorage to laminin 5 at 4 degrees C in epithelial cells of the skin and intestine. Transmembrane signaling through p80 is an early tyrosine phosphorylation event responsive to and possibly required for anchorage to laminin 5 by HFK and LS123 epithelial cells.
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Affiliation(s)
- Y Xia
- Department of Cell Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA
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