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1.  Synergistic Effect of Bone Marrow-Derived Mesenchymal Stem Cells and Platelet-Rich Plasma in Streptozotocin-Induced Diabetic Rats 
Annals of Dermatology  2014;26(1):1-10.
Diabetic wounds are a major clinical challenge, because minor skin wounds can lead to chronic, unhealed ulcers and ultimately result in infection, gangrene, or even amputation. Studies on bone marrow derived mesenchymal stem cells (BMSCs) and a series of growth factors have revealed their many benefits for wound healing and regeneration. Platelet-rich plasma (PRP) may improve the environment for BMSC development and differentiation. However, whether combined use of BMSCs and PRP may be more effective for accelerating diabetic ulcer healing remains unclear.
We investigated the efficacy of BMSCs and PRP for the repair of refractory wound healing in a diabetic rat model.
Forty-eight rats with diabetes mellitus induced by streptozotocin were divided into four groups: treatment with BMSCs plus PRP, BMSCs alone, PRP alone, phosphate buffered saline. The rate of wound closure was quantified. A histopathological study was conducted regarding wound depth and the skin edge at 7, 14, and 28 days after surgery.
Wound healing rates were significantly higher in the BMSC plus PRP group than in the other groups. The immunohistochemistry results showed that the expression of platelet/endothelial cell adhesion molecule 1, proliferating cell nuclear antigen, and transforming growth factor-β1 increased significantly in the BMSC plus PRP group compared to the other treatment groups. On day 7, CD68 expression increased significantly in the wounds of the BMSC plus PRP group, but decreased markedly at day 14 compared to the controls.
The combination of BMSCs and PRP aids diabetic wound repair and regeneration.
PMCID: PMC3956772  PMID: 24648680
Bone marrow-derived mesenchymal stem cell; Diabetes mellitus; Platelet-rich plasma; Wounds
2.  Enhanced skin wound healing by a sustained release of growth factors contained in platelet-rich plasma 
Experimental & Molecular Medicine  2011;43(11):622-629.
Platelet-rich plasma (PRP) contains growth factors that promote tissue regeneration. Previously, we showed that heparin-conjugated fibrin (HCF) exerts the sustained release of growth factors with affinity for heparin. Here, we hypothesize that treatment of skin wound with a mixture of PRP and HCF exerts sustained release of several growth factors contained in PRP and promotes skin wound healing. The release of fibroblast growth factor 2, platelet-derived growth factor-BB, and vascular endothelial growth factor contained in PRP from HCF was sustained for a longer period than those from PRP, calcium-activated PRP (C-PRP), or a mixture of fibrin and PRP (F-PRP). Treatment of full-thickness skin wounds in mice with HCF-PRP resulted in much faster wound closure as well as dermal and epidermal regeneration at day 12 compared to treatment with either C-PRP or F-PRP. Enhanced skin regeneration observed in HCF-PRP group may have been at least partially due to enhanced angiogenesis in the wound beds. Therefore, this method could be useful for skin wound treatment.
PMCID: PMC3249588  PMID: 21847007
angiogenesis inducing agents; endothelial growth factors; fibrin; fibroblast growth factor 2; heparin; neovascularization, physiologic; platelet-derived growth factor; platelet-rich plasma; wound healing
3.  Surgical Reconstruction of Radiation Injuries 
Advances in Wound Care  2014;3(1):25-37.
Significance: Patients with cancer receive benefits from radiation therapy; however, it may have adverse effects on normal tissue such as causing radiation-induced ulcer and osteoradionecrosis. The most reliable method to treat a radiation ulcer is wide excision of the affected tissue, followed by coverage with well-vascularized tissue. As usual, radiation-induced skin ulcers are due to therapeutic irradiation for residual cancer or lymph nodes; the locations of radiation ulcers are relatively limited, including the head, neck, chest wall, lumbar, groin, and sacral areas. Thus, suitable reconstructive methods vary according to functional and aesthetic conditions. I reviewed the practices and surgical results for radiation ulcers over the past 30 years, and present the recommended surgical methods for these hard-to-heal ulcers.
Recent Advances: At a minimum, flaps are required to treat radiation ulcers. Surgeons can recommend earlier debridement, followed by immediate coverage with axial-pattern musculocutaneous and fasciocutaneous flaps. Free flaps are also a useful soft tissue coverage option. The choice of flap varies with the location and size of the wounds.
Critical Issues: The most crucial procedure is the complete resection of the radiation-affected area, followed by coverage with well-vascularized tissue.
Future Directions: Recent developments in perforator flap techniques, which are defined as flaps with a blood supply from isolated perforating vessels of a stem artery, have allowed the surgeons to successfully resurface these difficult wounds with reduced morbidity.
PMCID: PMC3900101  PMID: 24761342
4.  Improvement of wound healing by water-filtered infrared-A (wIRA) in patients with chronic venous stasis ulcers of the lower legs including evaluation using infrared thermography 
Background: Water-filtered infrared-A (wIRA) is a special form of heat radiation with a high tissue-penetration and with a low thermal burden to the surface of the skin. wIRA is able to improve essential and energetically meaningful factors of wound healing by thermal and non-thermal effects.
Aim of the study: prospective study (primarily planned randomised, controlled, blinded, de facto with one exception only one cohort possible) using wIRA in the treatment of patients with recalcitrant chronic venous stasis ulcers of the lower legs with thermographic follow-up.
Methods: 10 patients (5 males, 5 females, median age 62 years) with 11 recalcitrant chronic venous stasis ulcers of the lower legs were treated with water-filtered infrared-A and visible light irradiation (wIRA(+VIS), Hydrosun® radiator type 501, 10 mm water cuvette, water-filtered spectrum 550–1400 nm) or visible light irradiation (VIS; only possible in one patient). The uncovered wounds of the patients were irradiated two to five times per week for 30 minutes at a standard distance of 25 cm (approximately 140 mW/cm2 wIRA and approximately 45 mW/cm2 VIS). Treatment continued for a period of up to 2 months (typically until closure or nearly closure of the ulcer). The main variable of interest was “percent change of ulcer size over time” including complete wound closure. Additional variables of interest were thermographic image analysis, patient’s feeling of pain in the wound, amount of pain medication, assessment of the effect of the irradiation (by patient and by clinical investigator), assessment of feeling of the wound area (by patient), assessment of wound healing (by clinical investigator) and assessment of the cosmetic state (by patient and by clinical investigator). For these assessments visual analogue scales (VAS) were used.
Results: The study showed a complete or nearly complete healing of lower leg ulcers in 7 patients and a clear reduction of ulcer size in another 2 of 10 patients, a clear reduction of pain and pain medication consumption (e.g. from 15 to 0 pain tablets per day), and a normalization of the thermographic image (before the beginning of the therapy typically hyperthermic rim of the ulcer with relative hypothermic ulcer base, up to 4.5°C temperature difference). In one patient the therapy of an ulcer of one leg was performed with the fully active radiator (wIRA(+VIS)), while the therapy of an ulcer of the other leg was made with a control group radiator (only VIS without wIRA), showing a clear difference in favour of the wIRA treatment. All mentioned VAS ratings improved remarkably during the period of irradiation treatment, representing an increased quality of life. Failures of complete or nearly complete wound healing were seen only in patients with arterial insufficiency, in smokers or in patients who did not have venous compression garment therapy.
Discussion and conclusions: wIRA can alleviate pain considerably (with an impressive decrease of the consumption of analgesics) and accelerate wound healing or improve a stagnating wound healing process and diminish an elevated wound exudation and inflammation both in acute and in chronic wounds (in this study shown in chronic venous stasis ulcers of the lower legs) and in problem wounds including infected wounds. In chronic recalcitrant wounds complete healing is achieved, which was not reached before. Other studies have shown that even without a disturbance of wound healing an acute wound healing process can be improved (e.g. reduced pain) by wIRA.
wIRA is a contact-free, easily used and pleasantly felt procedure without consumption of material with a good penetration effect, which is similar to solar heat radiation on the surface of the earth in moderate climatic zones. Wound healing and infection defence (e.g. granulocyte function including antibacterial oxygen radical formation of the granulocytes) are critically dependent on a sufficient energy supply (and on sufficient oxygen). The good clinical effect of wIRA on wounds and also on problem wounds and wound infections can be explained by the improvement of both the energy supply and the oxygen supply (e.g. for the granulocyte function). wIRA causes as a thermal effect in the tissue an improvement in three decisive factors: tissue oxygen partial pressure, tissue temperature and tissue blood flow. Besides this non-thermal effects of infrared-A by direct stimulation of cells and cellular structures with reactions of the cells have also been described. It is concluded that wIRA can be used to improve wound healing, to reduce pain, exudation, and inflammation and to increase quality of life.
PMCID: PMC2703263  PMID: 19675738
water-filtered infrared-A (wIRA); wound healing; chronic venous stasis ulcers of the lower legs; infrared thermography; thermographic image analysis; prospective study; visual analogue scales (VAS); reduction of pain; problem wounds; wound infections; energy supply; oxygen supply; tissue oxygen partial pressure; tissue temperature; tissue blood flow; quality of life
5.  Double-application of platelet-rich plasma on bone healing in rabbits 
Objective: Platelet-rich plasma (PRP) is considered to enhance bone formation especially at early stages of wound healing, depending on the limited and short life-span of platelets and growth factors. The aim of this study was to evaluate efficacy of double-application of PRP (DA-PRP) on bone healing in a rabbit calvarial defect model. Study design: Twenty-eight rabbits, each had two surgically prepared calvarial bone defects (10mm diameter), were included in this study and randomly divided into six groups. Defects (n=56) were treated with single-application of PRP (SA-PRP)(n=10), SA-PRP and beta-tricalciumphosphate (SA-PRP+TCP)(n=10), DA-PRP (n=8), DA-PRP and beta-tricalciumphosphate (DA-PRP+TCP)(n=8), beta-tricalciumphosphate (TCP)(n=10) or left empty (Control)(n=10). Animals were sacrificed at 30 days postoperatively. Results: The new bone (NB%) and defect fill (DF%) percentages were calculated from histological slides by image-analyzer software and statistically analysed. All test groups showed higher NB% than control, but differences among all groups were insignificant. The TCP treated groups had significantly higher DF% than groups treated without TCP, however the DF% differences between control, SA-PRP and DA-PRP or TCP, SA-PRP+TCP or DA-PRP+TCP were insignificant. Conclusion: Although new bone formation was histomorphologically remarkable at double-application PRP groups, statistical analyses of the histomorphometric data revealed no significant difference.
Key words: Platelet-Rich Plasma, double application, bone formation, wound healing.
PMCID: PMC3448207  PMID: 22157673
6.  Autologous Platelet Rich Plasma in Chronic Venous Ulcers: Study of 17 Cases 
Venous ulcers are wounds that are thought to occur due to improper functioning of venous valves, usually of the legs. They are the major cause of chronic wounds, occurring in 70% to 90% of chronic wound cases. The treatment of venous ulcers also entails substantial costs. Autologous platelet rich plasma (PRP) is a simple office based procedure which helps in enhancing the wound healing by releasing many growth factors like platelet derived growth factors, fibroblast derived growth factors and epidermal growth factors.
To study the efficacy of autologous platelet rich plasma in the management of chronic venous ulcer.
12 patients with 17 venous ulcers were treated with PRP and treatment outcome was measured by percentage of improvement in area and volume of the ulcer.
12 patients with 17 ulcers were treated with PRP. The mean age of the patients was 33.5 years (SD 9.82). 10 were males and 2 were females. The mean duration of the healing of the ulcers was in 5.1 weeks (SD 3.1). The mean percentage improvement in the area and volume of the ulcer was 94.7% (SD 11.12) and 95.6% (SD 10.19) respectively.
PRP is safe, simple and effective procedure in treating chronic venous ulcers
PMCID: PMC3764770  PMID: 24023432
Non healing; platelet rich plasma; venous ulcers
7.  A case report on the use of sustained release platelet-rich plasma for the treatment of chronic pressure ulcers 
Chronic pressure ulcers affect patient health, emotional state, and quality of life, causing considerable morbidity and mortality in addition to contributing to significant health care costs from lengthy hospitalizations to advanced home care and surgical care costs. The conventional treatment of these wounds can be slow due to their chronic inflammatory state and the senescence of local reparative cells. Platelet-rich plasma (PRP) therapy has been growing as a viable treatment alternative for a number of clinical applications and has potential benefit for use in chronic wounds. The sustained release of large quantities of autologous growth factors, cytokines, and other mediators found in PRP plus the favorable mononuclear cell profile of PRP may help us to stimulate wound healing and resolve chronic inflammation.
Three veterans with spinal cord injury (SCI), presenting with chronic stage IV pressure ulcers, were treated with a sustained release PRP therapy to stimulate wound healing.
PRP treatment consistently resulted in the formation of granulation tissue and improved vascularity for each of the three patients treated, while reducing the overall ulcer area and volume.
The controlled release of growth factors from PRP demonstrated a positive stimulatory effect on the healing rate of chronic pressure ulcers in individuals with SCI.
PMCID: PMC3066495  PMID: 21528636
Spinal cord injuries; Pressure ulcers; Tetraplegia; Paraplegia; Wound healing; Platelet-rich plasma therapy
8.  Chronic radiodermatitis following cardiac catheterisation: a report of two cases and a brief review of the literature 
Heart  1999;81(3):308-312.
Cardiac angiography produces one of the highest radiation exposures of any commonly used diagnostic x ray procedure. Recently, serious radiation induced skin injuries have been reported after repeated therapeutic interventional procedures using prolonged fluoroscopic imaging. Two male patients, aged 62 and 71 years, in whom chronic radiodermatitis developed one to two years after two consecutive cardiac catheterisation procedures are reported. Both patients had undergone lengthy procedures using prolonged fluoroscopic guidance in a limited number of projections. The resulting skin lesions were preceded, in one case, by an acute erythema and took the form of a delayed pigmented telangiectatic, indurated, or ulcerated plaque in the upper back or below the axilla whose site corresponded to the location of the x ray tube during cardiac catheterisation. Cutaneous side effects of radiation exposure result from direct damage to the irradiated tissue and have known thresholds. The diagnosis of radiation induced skin injury relies essentially on clinical and histopathological findings, location of skin lesions, and careful medical history. Interventional cardiologists should be aware of this complication, because chronic radiodermatitis may result in painful and resistant ulceration and eventually in squamous cell carcinoma.

 Keywords: catheterisation; angiography; radiation; radiodermatitis; skin injury
PMCID: PMC1728981  PMID: 10026359
9.  HGF Mediates the Anti-inflammatory Effects of PRP on Injured Tendons 
PLoS ONE  2013;8(6):e67303.
Platelet-rich plasma (PRP) containing hepatocyte growth factor (HGF) and other growth factors are widely used in orthopaedic/sports medicine to repair injured tendons. While PRP treatment is reported to decrease pain in patients with tendon injury, the mechanism of this effect is not clear. Tendon pain is often associated with tendon inflammation, and HGF is known to protect tissues from inflammatory damages. Therefore, we hypothesized that HGF in PRP causes the anti-inflammatory effects. To test this hypothesis, we performed in vitro experiments on rabbit tendon cells and in vivo experiments on a mouse Achilles tendon injury model. We found that addition of PRP or HGF decreased gene expression of COX-1, COX-2, and mPGES-1, induced by the treatment of tendon cells in vitro with IL-1β. Further, the treatment of tendon cell cultures with HGF antibodies reduced the suppressive effects of PRP or HGF on IL-1β-induced COX-1, COX-2, and mPGES-1 gene expressions. Treatment with PRP or HGF almost completely blocked the cellular production of PGE2 and the expression of COX proteins. Finally, injection of PRP or HGF into wounded mouse Achilles tendons in vivo decreased PGE2 production in the tendinous tissues. Injection of platelet-poor plasma (PPP) however, did not reduce PGE2 levels in the wounded tendons, but the injection of HGF antibody inhibited the effects of PRP and HGF. Further, injection of PRP or HGF also decreased COX-1 and COX-2 proteins. These results indicate that PRP exerts anti-inflammatory effects on injured tendons through HGF. This study provides basic scientific evidence to support the use of PRP to treat injured tendons because PRP can reduce inflammation and thereby reduce the associated pain caused by high levels of PGE2.
PMCID: PMC3696073  PMID: 23840657
10.  Platelet-rich plasma (PRP) in dental and oral surgery: from the wound healing to bone regeneration 
Platelet-rich plasma (PRP) is a new approach to tissue regeneration and it is becoming a valuable adjunct to promote healing in many procedures in dental and oral surgery, especially in aging patients. PRP derives from the centrifugation of the patient's own blood and it contains growth factors that influence wound healing, thereby playing an important role in tissue repairing mechanisms. The use of PRP in surgical practice could have beneficial outcomes, reducing bleeding and enhancing soft tissue healing and bone regeneration. Studies conducted on humans have yielded promising results regarding the application of PRP to many dental and oral surgical procedures (i.e. tooth extractions, periodontal surgery, implant surgery). The use of PRP has also been proposed in the management of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with the aim of enhancing wound healing and bone maturation. The aims of this narrative review are: i) to describe the different uses of PRP in dental surgery (tooth extractions and periodontal surgery) and oral surgery (soft tissues and bone tissue surgery, implant surgery and BRONJ surgery); and ii) to discuss its efficacy, efficiency and risk/benefit ratio. This review suggests that the use of PRP in the alveolar socket after tooth extractions is certainly capable of improving soft tissue healing and positively influencing bone regeneration but the latter effect seems to decrease a few days after the extraction. PRP has produced better results in periodontal therapy in association with other materials than when it is used alone. Promising results have also been obtained in implant surgery, when PRP was used in isolation as a coating material. The combination of necrotic bone curettage and PRP application seem to be encouraging for the treatment of refractory BRONJ, as it has proven successful outcomes with minimal invasivity. Since PRP is free from potential risks for patients, not difficult to obtain and use, it can be employed as a valid adjunct in many procedures in oral and dental surgery. However, further RCTs are required to support this evidence.
PMCID: PMC3683340  PMID: 23763951
PRP; Wound healing; Bone regeneration; Dental surgery; Oral surgery; Tooth extraction; Periodontal surgery; Implant surgery; BRONJ
11.  Cell Therapy for Wound Healing 
Journal of Korean Medical Science  2014;29(3):311-319.
In covering wounds, efforts should include utilization of the safest and least invasive methods with goals of achieving optimal functional and cosmetic outcome. The recent development of advanced wound healing technology has triggered the use of cells to improve wound healing conditions. The purpose of this review is to provide information on clinically available cell-based treatment options for healing of acute and chronic wounds. Compared with a variety of conventional methods, such as skin grafts and local flaps, the cell therapy technique is simple, less time-consuming, and reduces the surgical burden for patients in the repair of acute wounds. Cell therapy has also been developed for chronic wound healing. By transplanting cells with an excellent wound healing capacity profile to chronic wounds, in which wound healing cannot be achieved successfully, attempts are made to convert the wound bed into the environment where maximum wound healing can be achieved. Fibroblasts, keratinocytes, adipose-derived stromal vascular fraction cells, bone marrow stem cells, and platelets have been used for wound healing in clinical practice. Some formulations are commercially available. To establish the cell therapy as a standard treatment, however, further research is needed.
Graphical Abstract
PMCID: PMC3945123  PMID: 24616577
Cell-and Tissue-based Therapy; Wounds and Injuries; Tissue Engineering
12.  Therapy of chronic wounds with water-filtered infrared-A (wIRA) 
The central portion of chronic wounds is often hypoxic and relatively hypothermic, representing a deficient energy supply of the tissue, which impedes wound healing or even makes it impossible. Water-filtered infrared-A (wIRA) is a special form of heat radiation with a high tissue penetration and a low thermal load to the skin surface. wIRA produces a therapeutically usable field of heat and increases temperature, oxygen partial pressure and perfusion of the tissue. These three factors are decisive for a sufficient tissue supply with energy and oxygen and consequently as well for wound healing, especially in chronic wounds, and infection defense. wIRA acts both by thermal and thermic as well as by non-thermal and non-thermic effects. wIRA can advance wound healing or improve an impaired wound healing process and can especially enable wound healing in non-healing chronic wounds. wIRA can considerably alleviate the pain and diminish wound exudation and inflammation and can show positive immunomodulatory effects.
In a prospective, randomized, controlled study of 40 patients with chronic venous stasis ulcers of the lower legs irradiation with wIRA and visible light (VIS) accelerated the wound healing process (on average 18 vs. 42 days until complete wound closure, residual ulcer area after 42 days 0.4 cm² vs. 2.8 cm²) and led to a reduction of the required dose of pain medication in comparison to the control group of patients treated with the same standard care (wound cleansing, wound dressing with antibacterial gauze, and compression garment therapy) without the concomitant irradiation.
Another prospective study of 10 patients with non-healing chronic venous stasis ulcers of the lower legs included extensive thermographic investigation. Therapy with wIRA(+VIS) resulted in a complete or almost complete wound healing in 7 patients and a marked reduction of the ulcer size in another 2 of the 10 patients, a clear reduction of pain and required dose of pain medication, and a normalization of the thermographic image.
In a current prospective, randomized, controlled, blinded study patients with non-healing chronic venous stasis ulcers of the lower legs are treated with compression garment therapy, wound cleansing, wound dressings and 30 minutes irradiation five times per week over 9 weeks. A preliminary analysis of the first 23 patients of this study has shown in the group with wIRA(+VIS) compared to a control group with VIS an advanced wound healing, an improved granulation and in the later phase of treatment a decrease of the bacterial burden.
Some case reports have demonstrated that wIRA can also be used for mixed arterial-venous ulcers or arterial ulcers, if irradiation intensity is chosen appropriately low and if irradiation is monitored carefully. wIRA can be used concerning decubital ulcers both in a preventive and in a therapeutic indication. wIRA can improve the resorption of topically applied substances also on wounds.
An irradiation with VIS and wIRA presumably acts with endogenous protoporphyrin IX (or protoporphyrin IX of bacteria) virtually similar as a mild photodynamic therapy (endogenous PDT-like effect). This could lead to improved cell regeneration and wound healing and to antibacterial effects.
In conclusion, these results indicate that wIRA generally should be considered for the treatment of chronic wounds.
PMCID: PMC2831243  PMID: 20204086
water-filtered infrared-A (wIRA); wound healing; chronic wounds; chronic venous stasis ulcers of the lower legs; prospective, randomized, controlled, blinded study; reduction of pain; problem wounds; wound infections; infection defense; wound exudation; inflammation; energy supply; oxygen supply; tissue oxygen partial pressure; tissue temperature; tissue blood flow; thermal and non-thermal effects; thermic and non-thermic effects; visual analog scales (VAS); infrared thermography; thermographic image analysis; quality of life
13.  In Vivo Comparison of the Bone Regeneration Capability of Human Bone Marrow Concentrates vs. Platelet-Rich Plasma 
PLoS ONE  2012;7(7):e40833.
Bone marrow aspirate concentrate (BMAC) including high densities of stem cells and progenitor cells may possess a stronger bone regenerative capability compared with Platelet-rich plasma (PRP), which contains enriched growth factors. The objective of this study was to evaluate the effects of human BMAC and PRP in combination with β-tricalcium phosphate (β-TCP) on promoting initial bone augmentation in an immunodeficient mouse model.
Methodology/Principal Findings
BMAC and PRP were concentrated with an automated blood separator from the bone marrow and peripheral blood aspirates. β-TCP particles were employed as a scaffold to carry cells. After cell counting and FACS characterization, three groups of nude mice (BMAC+TCP, PRP+TCP, and a TCP control) were implanted with graft materials for onlay placement on the cranium. Samples were harvested after 4 weeks, and serial sections were prepared. We observed the new bone on light microscopy and performed histomorphometric analysis. After centrifugation, the concentrations of nucleated cells and platelets in BMAC were increased by factors of 2.8±0.8 and 5.3±2.4, respectively, whereas leucocytes and platelets in PRP were increased by factors of 4.1±1.8 and 4.4±1.9, respectively. The concentrations of CD34-, CD271-, CD90-, CD105-, and CD146-positive cells were markedly increased in both BMAC and PRP. The percentage of new bone in the BMAC group (7.6±3.9%) and the PRP group (7.2±3.8%) were significantly higher than that of TCP group (2.7±1.4%). Significantly more bone cells in the new bone occurred in sites transplanted with BMAC (552±257) and PRP (491±211) compared to TCP alone (187±94). But the difference between the treatment groups was not significant.
Both human BMACs and PRP may provide therapeutic benefits in bone tissue engineering applications. These fractions possess a similar ability to enhance early-phase bone regeneration.
PMCID: PMC3395629  PMID: 22808272
14.  Autologous Platelet Rich Plasma After Third Molar Surgery: A Comparative Study 
This study is an attempt to evaluate the use of autologous platelet rich plasma (PRP) to promote wound healing and osseous regeneration in human third molar extraction sockets.
Materials and method
PRP was prepared after two centrifugation and the gelling agent used was freshly prepared 10% calcium chloride.PRP gel was placed in one of the extracted sockets of bilateral impacted mandibular third molars. IOPA Xrays were used to evaluate the wound dehiscence, probing depth, bone density & alveolar bone level after 1st, 2nd and 7th day and 3rd & 6th month respectively.
On evaluation, it was found that PRP grafted sockets showed dehiscence in 8% cases. The decrease in alveolar bone level was highly significant in PRP grafted sockets in 3rd and 6th month post operatively. There was significant difference between pre-operative density of adjacent bone and bone formed in extraction sockets at 3rd and 6th month in PRP grafted sockets. There was significant reduction in probing depth from initial period to 3 and 6 months in both the groups, but PRP grafted sockets showed greater decrease in probing depth.
PRP is an inexpensive and widely available modality to minimize postoperative complication and enhance both hard and soft tissue healing potentials. This autologous product eliminates concern about immunogenic reaction and disease transmission. Its beneficial outcomes in dental clinic, including decrease in bleeding and rapid wound healing hold promise for further procedures.PRP is thus a new application in tissue engineering and developing area for clinician and researchers.
PMCID: PMC3386415  PMID: 23730070
Autologous; Growth factors; Platelet-rich plasma; Bone density; Soft tissue healing
15.  The Composite of Bone Marrow Concentrate and PRP as an Alternative to Autologous Bone Grafting 
PLoS ONE  2014;9(6):e100143.
One possible alternative to the application of autologous bone grafts represents the use of autologous bone marrow concentrate (BMC). The purpose of our study was to evaluate the potency of autologous platelet-rich plasma (PRP) in combination with BMC. In 32 mini-pigs a metaphyseal critical-size defect was surgically created at the proximal tibia. The animals were allocated to four treatment groups of eight animals each (1. BMC+CPG group, 2. BMC+CPG+PRP group, 3. autograft group, 4. CPG group). In the BMC+CPG group the defect was filled with autologous BMC in combination with calcium phosphate granules (CPG), whereas in the BMC+CPG+PRP group the defect was filled with the composite of autologous BMC, CPG and autologous PRP. In the autograft group the defect was filled with autologous cancellous graft, whereas in the CPG group the defect was filled with CPG solely. After 6 weeks radiological and histomorphometrical analysis showed significantly more new bone formation in the BMC+CPG+PRP group compared to the BMC+CPG group and the CPG group. There were no significant differences between the BMC+CPG+PRP group and the autograft group. In the PRP platelets were enriched significantly about 4.7-fold compared to native blood. In BMC the count of mononuclear cells increased significantly (3.5-fold) compared to the bone marrow aspirate. This study demonstrates that the composite of BMC+CPG+PRP leads to a significantly higher bone regeneration of critical-size defects at the proximal tibia in mini-pigs than the use of BMC+CPG without PRP. Furthermore, within the limits of the present study the composite BMC+CPG+PRP represents a comparable alternative to autologous bone grafting.
PMCID: PMC4064995  PMID: 24950251
16.  Characterization of the cytokine profile of platelet rich plasma (PRP) and PRP-induced cell proliferation and migration: Upregulation of matrix metalloproteinase-1 and -9 in HaCaT cells 
The Korean Journal of Hematology  2011;46(4):265-273.
The underlying rationale of platelet rich plasma (PRP) therapy is that an injection of concentrated PRP at the site of injury may promote tissue repair via cytokine release from platelets. The molecular mechanisms of PRP therapy in the skin wound healing process are not well understood at present, and would benefit from clarification.
PRP was stimulated with angonists for 5 min, and cytokine profile analysis was performed. To investigate the wound healing activity of PRP, cell proliferation and migration analyses were performed in skin cells. The effects of PRP were analyzed on the expression and activity of matrix metalloproteinase (MMP)-1, -2, -9, and the activation of transcription factors.
Thrombin was found to be a strong stimulator of PRP activation to release growth factors and chemokines. PRP induced cell proliferation and migration in HUVECs, HaCaT cells, and HDFs, as well as MMP-1and MMP-9 expression in HaCaT cells, but PRP did not have a significant effect on the expression or activity of MMPs in HDFs. The transcription factors, including signal transducer and activator of transcription-3 (STAT-3) were found to be phosphorylated following PRP treatment in HaCaT cells.
In this study, we have identified the cytokine profile of activated PRP after agonist stimulation. We have shown that PRP plays an active role in promoting the proliferation and migration of skin cells via the regulation of MMPs, and this may be applicable to the future development of PRP therapeutics to enhance skin wound healing.
PMCID: PMC3259519  PMID: 22259633
Platelet rich plasma (PRP); Wound healing; Cytokine profile; Cell proliferation; Cell migration; Matrix metalloproteinase
17.  Treatment of Radiation Injury 
Advances in Wound Care  2014;3(1):1-11.
Significance: Radiation exposure as a result of radiation treatment, accident, or terrorism may cause serious problems such as deficiency due to necrosis or loss of function, fibrosis, or intractable ulcers in the tissues and organs. When the skin, bone, oral mucous membrane, guts, or salivary glands are damaged by ionizing radiation, the management and treatment are very lengthy and difficult.
Critical Issues: In severe and irreversible injuries, surgery remains the mainstay of treatment. Several surgical procedures, such as debridement, skin grafting, and local and free-vascularized flaps, are widely used.
Recent Advances: In specific cases of major morbidity or in high-risk patients, a newly developed therapy using a patient's own stem cells is safe and effective. Adipose tissue, normally a rich source of mesenchymal stem cells, which are similar to those from the bone marrow, can be harvested, since the procedure is easy, and abundant tissue can be obtained with minimal invasiveness.
Future Directions: Based on the molecular basis of radiation injuries, several prospective treatments are under development. Single-nucleotide polymorphisms focus on an individual's sensitivity to radiation in radiogenomics, and the pathology of radiation fibrosis or the effect of radiation on wound healing is being studied and will lead to new insight into the treatment of radiation injuries. Protectors and mitigators are being actively investigated in terms of the timing of administration or dose.
PMCID: PMC3900019  PMID: 24761339
18.  Negative Pressure Wound Therapy 
Executive Summary
This review was conducted to assess the effectiveness of negative pressure wound therapy.
Clinical Need: Target Population and Condition
Many wounds are difficult to heal, despite medical and nursing care. They may result from complications of an underlying disease, like diabetes; or from surgery, constant pressure, trauma, or burns. Chronic wounds are more often found in elderly people and in those with immunologic or chronic diseases. Chronic wounds may lead to impaired quality of life and functioning, to amputation, or even to death.
The prevalence of chronic ulcers is difficult to ascertain. It varies by condition and complications due to the condition that caused the ulcer. There are, however, some data on condition-specific prevalence rates; for example, of patients with diabetes, 15% are thought to have foot ulcers at some time during their lives. The approximate community care cost of treating leg ulcers in Canada, without reference to cause, has been estimated at upward of $100 million per year.
Surgically created wounds can also become chronic, especially if they become infected. For example, the reported incidence of sternal wound infections after median sternotomy is 1% to 5%. Abdominal surgery also creates large open wounds. Because it is sometimes necessary to leave these wounds open and allow them to heal on their own (secondary intention), some may become infected and be difficult to heal.
Yet, little is known about the wound healing process, and this makes treating wounds challenging. Many types of interventions are used to treat wounds.
Current best practice for the treatment of ulcers and other chronic wounds includes debridement (the removal of dead or contaminated tissue), which can be surgical, mechanical, or chemical; bacterial balance; and moisture balance. Treating the cause, ensuring good nutrition, and preventing primary infection also help wounds to heal. Saline or wet-to-moist dressings are reported as traditional or conventional therapy in the literature, although they typically are not the first line of treatment in Ontario. Modern moist interactive dressings are foams, calcium alginates, hydrogels, hydrocolloids, and films. Topical antibacterial agents—antiseptics, topical antibiotics, and newer antimicrobial dressings—are used to treat infection.
The Technology Being Reviewed
Negative pressure wound therapy is not a new concept in wound therapy. It is also called subatmospheric pressure therapy, vacuum sealing, vacuum pack therapy, and sealing aspirative therapy.
The aim of the procedure is to use negative pressure to create suction, which drains the wound of exudate (i.e., fluid, cells, and cellular waste that has escaped from blood vessels and seeped into tissue) and influences the shape and growth of the surface tissues in a way that helps healing. During the procedure, a piece of foam is placed over the wound, and a drain tube is placed over the foam. A large piece of transparent tape is placed over the whole area, including the healthy tissue, to secure the foam and drain the wound. The tube is connected to a vacuum source, and fluid is drawn from the wound through the foam into a disposable canister. Thus, the entire wound area is subjected to negative pressure. The device can be programmed to provide varying degrees of pressure either continuously or intermittently. It has an alarm to alert the provider or patient if the pressure seal breaks or the canister is full.
Negative pressure wound therapy may be used for patients with chronic and acute wounds; subacute wounds (dehisced incisions); chronic, diabetic wounds or pressure ulcers; meshed grafts (before and after); or flaps. It should not be used for patients with fistulae to organs/body cavities, necrotic tissue that has not been debrided, untreated osteomyelitis, wound malignancy, wounds that require hemostasis, or for patients who are taking anticoagulants.
Review Strategy
The inclusion criteria were as follows:
Randomized controlled trial (RCT) with a sample size of 20 or more
Human study
Published in English
Summary of Findings
Seven international health technology assessments on NPWT were identified. Included in this list of health technology assessments is the original health technology review on NPWT by the Medical Advisory Secretariat from 2004. The Medical Advisory Secretariat found that the health technology assessments consistently reported that NPWT may be useful for healing various types of wounds, but that its effectiveness could not be empirically quantified because the studies were poorly done, the patient populations and outcome measures could not be compared, and the sample sizes were small.
Six RCTs were identified that compared NPWT to standard care. Five of the 6 studies were of low or very low quality according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. The low and very low quality RCTs were flawed owing to small sample sizes, inconsistent reporting of results, and patients lost to follow-up. The highest quality study, which forms the basis of this health technology policy assessment, found that:
There was not a statistically significant difference (≥ 20%) between NPWT and standard care in the rate of complete wound closure in patients who had complete wound closure but did not undergo surgical wound closure (P = .15).
The authors of this study did not report the length of time to complete wound closure between NPWT and standard care in patients who had complete wound closure but who did not undergo surgical wound closure
There was no statistically significant difference (≥ 20%) in the rate of secondary amputations between the patients that received NPWT and those that had standard care (P = .06)
There may be an increased risk of wound infection in patients that receive NPWT compared with those that receive standard care.
Based on the evidence to date, the clinical effectiveness of NPWT to heal wounds is unclear. Furthermore, saline dressings are not standard practice in Ontario, thereby rendering the literature base irrelevant in an Ontario context. Nonetheless, despite the lack of methodologically sound studies, NPWT has diffused across Ontario.
Discussions with Ontario clinical experts have highlighted some deficiencies in the current approach to wound management, especially in the community. Because NPWT is readily available, easy to administer, and may save costs, compared with multiple daily conventional dressing changes, it may be used inappropriately. The discussion group highlighted the need to put in place a coordinated, multidisciplinary strategy for wound care in Ontario to ensure the best, continuous care of patients.
PMCID: PMC3379164  PMID: 23074484
19.  Bone Marrow Aspiration Concentrate and Platelet Rich Plasma for Osteochondral Repair in a Porcine Osteochondral Defect Model 
PLoS ONE  2013;8(8):e71602.
Bone marrow aspiration concentrate (BMAC) may possess a high potency for cartilage and osseous defect healing because it contains stem cells and multiple growth factors. Alternatively, platelet rich plasma (PRP), which contains a cocktail of multiple growth factors released from enriched activated thrombocytes may potentially stimulate the mesenchymal stem cells (MSCs) in bone marrow to proliferate and differentiate.
A critical size osteochondral defect (10×6 mm) in both medial femoral condyles was created in 14 Goettinger mini-pigs. All animals were randomized into the following four groups: biphasic scaffold alone (TRUFIT BGS, Smith & Nephew, USA), scaffold with PRP, scaffold with BMAC and scaffold in combination with BMAC and PRP. After 26 weeks all animals were euthanized and histological slides were cut, stained and evaluated using a histological score and immunohistochemistry.
The thrombocyte number was significantly increased (p = 0.049) in PRP compared to whole blood. In addition the concentration of the measured growth factors in PRP such as BMP-2, BMP-7, VEGF, TGF-β1 and PDGF were significantly increased when compared to whole blood (p<0.05). In the defects of the therapy groups areas of chondrogenic tissue were present, which stained blue with toluidine blue and positively for collagen type II. Adding BMAC or PRP in a biphasic scaffold led to a significant improvement of the histological score compared to the control group, but the combination of BMAC and PRP did not further enhance the histological score.
The clinical application of BMAC or PRP in osteochondral defect healing is attractive because of their autologous origin and cost-effectiveness. Adding either PRP or BMAC to a biphasic scaffold led to a significantly better healing of osteochondral defects compared with the control group. However, the combination of both therapies did not further enhance healing.
PMCID: PMC3741121  PMID: 23951201
20.  Effect of Platelet-Rich Plasma on Chondrogenic Differentiation in Three-Dimensional Culture 
Platelet-rich plasma (PRP) may have the potential to enhance articular cartilage regeneration through release of growth factors including transforming growth factor isoforms. The purpose of this study was to investigate the potential for PRP to stimulate chondrogenic differentiation in three-dimensional PRP hydrogel constructs. Allogenic PRP was prepared using a double centrifugation protocol which resulted in a platelet concentration approximately 250% above baseline. Canine marrow stromal cells were encapsulated at 6.8×106 cells/ml in either 2% sodium alginate or in a 3:1 mixture of freshly prepared PRP and 2% alginate. PRP and alginate beads were cultured in chemically defined chondrogenic medium with and without 10 ng/ml TGF-β3. PRP cultures were additionally supplemented with frozen-thawed PRP. In the absence of TGF-β3, PRP had a mild stimulatory effect on cell proliferation. PRP did not stimulate cell proliferation in the presence of TGF-β3. Cells exposed to TGF-β3 accumulated significantly more GAG/DNA than those which were not, but there was not a statistically significant difference between alginate and PRP. Total collagen content was greater in PRP than in alginate, regardless of TGF-β3. Chondrogenesis in PRP was qualitatively and spatially different than that which occurred in conventional alginate beads and was characterized by isolated centers of intense chondrogenesis. Overall the results demonstrate that PRP alone weakly promotes chondroinduction of marrow stromal cells, and the effect is greatly augmented by TGF-β3.
PMCID: PMC4023405  PMID: 24843389
Chondroinduction; hydrogel culture; mesenchymal stem cells; platelet-rich plasma.
21.  Pressure Ulcer Prevention 
Executive Summary
In April 2008, the Medical Advisory Secretariat began an evidence-based review of the literature concerning pressure ulcers.
Please visit the Medical Advisory Secretariat Web site, to review these titles that are currently available within the Pressure Ulcers series.
Pressure ulcer prevention: an evidence based analysis
The cost-effectiveness of prevention strategies for pressure ulcers in long-term care homes in Ontario: projections of the Ontario Pressure Ulcer Model (field evaluation)
Management of chronic pressure ulcers: an evidence-based analysis (anticipated pubicstion date - mid-2009)
A pressure ulcer, also known as a pressure sore, decubitus ulcer, or bedsore, is defined as a localized injury to the skin/and or underlying tissue occurring most often over a bony prominence and caused by pressure, shear, or friction, alone or in combination. (1) Those at risk for developing pressure ulcers include the elderly and critically ill as well as persons with neurological impairments and those who suffer conditions associated with immobility. Pressure ulcers are graded or staged with a 4-point classification system denoting severity. Stage I represents the beginnings of a pressure ulcer and stage IV, the severest grade, consists of full thickness tissue loss with exposed bone, tendon, and or muscle. (1)
In a 2004 survey of Canadian health care settings, Woodbury and Houghton (2) estimated that the prevalence of pressure ulcers at a stage 1 or greater in Ontario ranged between 13.1% and 53% with nonacute health care settings having the highest prevalence rate (Table 1).
Executive Summary Table 1: Prevalence of Pressure Ulcers*
CI indicates confidence interval.
Nonacute care included sub-acute care, chronic care, complex continuing care, long-term care, and nursing home care.
Mixed health care includes a mixture of acute, nonacute, and/or community care health care delivery settings.
Pressure ulcers have a considerable economic impact on health care systems. In Australia, the cost of treating a single stage IV ulcer has been estimated to be greater than $61,000 (AUD) (approximately $54,000 CDN), (3) while in the United Kingdom the total cost of pressure ulcers has been estimated at £1.4–£2.1 billion annually or 4% of the National Health Service expenditure. (4)
Because of the high physical and economic burden of pressure ulcers, this review was undertaken to determine which interventions are effective at preventing the development of pressure ulcers in an at-risk population.
Review Strategy
The main objective of this systematic review is to determine the effectiveness of pressure ulcer preventive interventions including Risk Assessment, Distribution Devices, Nutritional Supplementation, Repositioning, and Incontinence Management.
A comprehensive literature search was completed for each of the above 5 preventive interventions. The electronic databases searched included MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature. As well, the bibliographic references of selected studies were searched. All studies meeting explicit inclusion and exclusion criteria for each systematic review section were retained and the quality of the body of evidence was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) system. (5) Where appropriate, a meta-analysis was undertaken to determine the overall estimate of effect of the preventive intervention under review.
Summary of Findings
Risk Assessment
There is very low quality evidence to support the hypothesis that allocating the type of pressure-relieving equipment according to the person’s level of pressure ulcer risk statistically decreases the incidence of pressure ulcer development. Similarly, there is very low quality evidence to support the hypothesis that incorporating a risk assessment into nursing practice increases the number of preventative measures used per person and that these interventions are initiated earlier in the care continuum.
Pressure Redistribution Devices
There is moderate quality evidence that the use of an alternative foam mattress produces a relative risk reduction (RRR) of 69% in the incidence of pressure ulcers compared with a standard hospital mattress. The evidence does not support the superiority of one particular type of alternative foam mattress.
There is very low quality evidence that the use of an alternating pressure mattress is associated with an RRR of 71% in the incidence of grade 1 or 2 pressure ulcers. Similarly, there is low quality evidence that the use of an alternating pressure mattress is associated with an RRR of 68% in the incidence of deteriorating skin changes.
There is moderate quality evidence that there is a statistically nonsignificant difference in the incidence of grade 2 pressure ulcers between persons using an alternating pressure mattress and those using an alternating pressure overlay.
There is moderate quality evidence that the use of an Australian sheepskin produces an RRR of 58% in the incidence of pressure ulcers grade 1 or greater. There is also evidence that sheepskins are uncomfortable to use. The Pressure Ulcer Advisory Panel noted that, in general, sheepskins are not a useful preventive intervention because they bunch up in a patient’s bed and may contribute to wound infection if not properly cleaned, and this reduces their acceptability as a preventive intervention.
There is very low quality evidence that the use of a Micropulse System alternating pressure mattress used intra operatively and postoperatively produces an RRR of 79% in the incidence of pressure ulcers compared with a gel-pad used intraoperatively and a standard hospital mattress used postoperatively (standard care). It is unclear if this effect is due to the use of the alternating pressure mattress intraoperatively or postoperatively or if indeed it must be used in both patient care areas.
There is low quality evidence that the use of a vesico-elastic polymer pad (gel pad) on the operating table for surgeries of at least 90 minutes’ duration produces a statistically significant RRR of 47% in the incidence of pressure ulcers grade 1 or greater compared with a standard operating table foam mattress.
There is low quality evidence that the use of an air suspension bed in the intensive care unit (ICU) for stays of at least 3 days produces a statistically significant RRR of 76% in the incidence of pressure ulcers compared with a standard ICU bed.
There is very low quality evidence that the use of an alternating pressure mattress does not statistically reduce the incidence of pressure ulcers compared with an alternative foam mattress.
Nutritional Supplementation
There is very low quality evidence supporting an RRR of 15% in the incidence of pressure ulcers when nutritional supplementation is added to a standard hospital diet.
There is low quality evidence supporting the superiority of a 4-hourly turning schedule with a vesico-elastic polyurethane foam mattress compared with a 2-hourly or 3-hourly turning schedule and a standard foam mattress to reduce the incidence of grade 1 or 2 pressure ulcers.
Incontinence Management
There is very low quality evidence supporting the benefit of a structured skin care protocol to reduce the incidence of grade 1 or 2 pressure ulcers in persons with urinary and/or fecal incontinence.
There is low quality evidence supporting the benefit of a pH-balanced cleanser compared with soap and water to reduce the incidence of grade 1 or 2 pressure ulcers in persons with urinary and fecal incontinence.
There is moderate quality evidence that an alternative foam mattress is effective in preventing the development of pressure ulcers compared with a standard hospital foam mattress.
However, overall there remains a paucity of moderate or higher quality evidence in the literature to support many of the preventive interventions. Until better quality evidence is available, pressure ulcer preventive care must be guided by expert opinion for those interventions where low or very low quality evidence supports the effectiveness of such interventions.
Confidence interval
Grading of Recommendation Assessment, Development, and Evaluation
Intensive care unit
Medical Advisory Secretariat
National Pressure Ulcer Advisory Panel
Risk assessment scale
Randomized controlled trial
Registered Nurses Association of Ontario
Relative risk
Relative risk reduction
PMCID: PMC3377566  PMID: 23074524
22.  Limb salvage surgery 
The threat of lower limb loss is seen commonly in severe crush injury, cancer ablation, diabetes, peripheral vascular disease and neuropathy. The primary goal of limb salvage is to restore and maintain stability and ambulation. Reconstructive strategies differ in each condition such as: Meticulous debridement and early coverage in trauma, replacing lost functional units in cancer ablation, improving vascularity in ischaemic leg and providing stable walking surface for trophic ulcer. The decision to salvage the critically injured limb is multifactorial and should be individualised along with laid down definitive indications. Early cover remains the standard of care, delayed wound coverage not necessarily affect the final outcome. Limb salvage is more cost-effective than amputations in a long run. Limb salvage is the choice of procedure over amputation in 95% of limb sarcoma without affecting the survival. Compound flaps with different tissue components, skeletal reconstruction; tendon transfer/reconstruction helps to restore function. Adjuvant radiation alters tissue characters and calls for modification in reconstructive plan. Neuropathic ulcers are wide and deep often complicated by osteomyelitis. Free flap reconstruction aids in faster healing and provides superior surface for offloading. Diabetic wounds are primarily due to neuropathy and leads to six-fold increase in ulcerations. Control of infections, aggressive debridement and vascular cover are the mainstay of management. Endovascular procedures are gaining importance and have reduced extent of surgery and increased amputation free survival period. Though the standard approach remains utilising best option in the reconstruction ladder, the recent trend shows running down the ladder of reconstruction with newer reliable local flaps and negative wound pressure therapy.
PMCID: PMC3901908  PMID: 24501463
Limb salvage; limb trauma; lower limb reconstruction; foot ulcers
23.  Platelet Rich Fibrin Matrix Improves Wound Angiogenesis via Inducing Endothelial Cell Proliferation 
The economic, social and public health burden of chronic ulcers and other compromised wounds are enormous and rapidly increasing with the aging population. The growth factors derived from platelets play an important role in tissue remodeling including neovascularization. Platelet-rich plasma (PRP) has been utilized and studied for the last four decades. Platelet gel and fibrin sealant, derived from PRP mixed with thrombin and calcium chloride, have been exogenously applied to tissues to promote wound healing, bone growth, hemostasis and tissue sealing. In this study we first characterized recovery and viability of as well as growth factor release from platelets in a novel preparation of platelet gel and fibrin matrix, namely, platelet rich fibrin matrix (PRFM). Next, the effect of PRFM application in a delayed model of ischemic wound angiogenesis was investigated. The study for the first-time shows the kinetics of the viability of platelet embedded fibrin matrix. A slow and steady release of growth factors from PRFM was observed. The VEGF released from PRFM was primarily responsible for endothelial mitogenic response via ERK activation pathway. Finally, this preparation of PRFM effectively induced endothelial cell proliferation and improved wound angiogenesis in chronic wounds, providing evidence of probable mechanisms of action of PRFM in healing of chronic ulcers.
PMCID: PMC3623798  PMID: 22092846
platelet rich plasma (PRP); wound healing; angiogenesis; autologous platelet gels; ischemic wounds
24.  Cascade® Autologous System Platelet-Rich Fibrin Matrix in the Treatment of Chronic Leg Ulcers 
Advances in Wound Care  2012;1(1):52-55.
Lower extremity ulcers (venous, diabetic) are often unresponsive to standard treatment. Various systemic and local cellular, vascular, and anatomical factors can result in nonhealing wounds that are refractory to normal healing processes and standard care.
Several published wound care guidelines strongly suggest that if an ulcer does not respond to standard good wound care within 4 weeks, then advanced wound therapies should be considered. These advanced therapies include wound bed preparation agents (negative wound pressure therapy, hyperbaric oxygen), recombinant growth factors, or bioengineered cell therapies.
New Technology
The Cascade® system produces platelet-rich fibrin matrix (PRFM), a novel autologous sterile biologic, produced at the bedside from a small volume (18 mL) of the patient's own blood by using Vacutainer® separation technology optimized for fibrin and platelet isolation. Prepared as an easy to apply, suturable membrane, without the use of exogenous thrombin, PRFM consists of a dense cross-linked fibrin lattice containing intact, viable platelets with their full complement of platelet-derived growth factors.
Indications for Use
From the FDA 510(k) clearance: The Cascade system “is designed to be used for the safe and rapid preparation of autologous platelet-rich plasma from a small sample of blood at the patient point of care.” PRFM has been used to successfully treat severe venous leg ulcer (VLU), neuropathic diabetic foot ulcer (DFU), mixed arterial and Charcot-deformity associated foot ulcers.
When treating venous or DFUs, the Cascade system should be used together with standard wound care practice (therapeutic compression for VLU and weight off-loading, debridement, and infection control for DFU) in patients with an adequate blood supply to the lower limb.
PMCID: PMC3839008  PMID: 24527280
25.  Management of Chronic Pressure Ulcers 
Executive Summary
In April 2008, the Medical Advisory Secretariat began an evidence-based review of the literature concerning pressure ulcers.
Please visit the Medical Advisory Secretariat Web site, to review these titles that are currently available within the Pressure Ulcers series.
Pressure ulcer prevention: an evidence based analysis
The cost-effectiveness of prevention strategies for pressure ulcers in long-term care homes in Ontario: projections of the Ontario Pressure Ulcer Model (field evaluation)
Management of chronic pressure ulcers: an evidence-based analysis
The Medical Advisory Secretariat (MAS) conducted a systematic review on interventions used to treat pressure ulcers in order to answer the following questions:
Do currently available interventions for the treatment of pressure ulcers increase the healing rate of pressure ulcers compared with standard care, a placebo, or other similar interventions?
Within each category of intervention, which one is most effective in promoting the healing of existing pressure ulcers?
A pressure ulcer is a localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in conjunction with shear and/or friction. Many areas of the body, especially the sacrum and the heel, are prone to the development of pressure ulcers. People with impaired mobility (e.g., stroke or spinal cord injury patients) are most vulnerable to pressure ulcers. Other factors that predispose people to pressure ulcer formation are poor nutrition, poor sensation, urinary and fecal incontinence, and poor overall physical and mental health.
The prevalence of pressure ulcers in Ontario has been estimated to range from a median of 22.1% in community settings to a median of 29.9% in nonacute care facilities. Pressure ulcers have been shown to increase the risk of mortality among geriatric patients by as much as 400%, to increase the frequency and duration of hospitalization, and to decrease the quality of life of affected patients. The cost of treating pressure ulcers has been estimated at approximately $9,000 (Cdn) per patient per month in the community setting. Considering the high prevalence of pressure ulcers in the Ontario health care system, the total cost of treating pressure ulcers is substantial.
Wounds normally heal in 3 phases (inflammatory phase, a proliferative phase of new tissue and matrix formation, and a remodelling phase). However, pressure ulcers often fail to progress past the inflammatory stage. Current practice for treating pressure ulcers includes treating the underlying causes, debridement to remove necrotic tissues and contaminated tissues, dressings to provide a moist wound environment and to manage exudates, devices and frequent turning of patients to provide pressure relief, topical applications of biologic agents, and nutritional support to correct nutritional deficiencies. A variety of adjunctive physical therapies are also in use.
Health technology assessment databases and medical databases were searched from 1996 (Medline), 1980 (EMBASE), and 1982 (CINAHL) systematically up to March 2008 to identify randomized controlled trials (RCTs) on the following treatments of pressure ulcers: cleansing, debridement, dressings, biological therapies, pressure-relieving devices, physical therapies, nutritional therapies, and multidisciplinary wound care teams. Full literature search strategies are reported in appendix 1. English-language studies in previous systematic reviews and studies published since the last systematic review were included if they had more than 10 subjects, were randomized, and provided objective outcome measures on the healing of pressure ulcers. In the absence of RCTs, studies of the highest level of evidence available were included. Studies on wounds other than pressure ulcers and on surgical treatment of pressure ulcers were excluded. A total of 18 systematic reviews, 104 RCTs, and 4 observational studies were included in this review.
Data were extracted from studies using standardized forms. The quality of individual studies was assessed based on adequacy of randomization, concealment of treatment allocation, comparability of groups, blinded assessment, and intention-to-treat analysis. Meta-analysis to estimate the relative risk (RR) or weighted mean difference (WMD) for measures of healing was performed when appropriate. A descriptive synthesis was provided where pooled analysis was not appropriate or not feasible. The quality of the overall evidence on each intervention was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) criteria.
Findings from the analysis of the included studies are summarized below:
There is no good trial evidence to support the use of any particular wound cleansing solution or technique for pressure ulcers.
There was no evidence that debridement using collagenase, dextranomer, cadexomer iodine, or maggots significantly improved complete healing compared with placebo.
There were no statistically significant differences between enzymatic or mechanical debridement agents with the following exceptions:
Papain urea resulted in better debridement than collagenase.
Calcium alginate resulted in a greater reduction in ulcer size compared to dextranomer.
Adding streptokinase/streptodornase to hydrogel resulted in faster debridement.
Maggot debridement resulted in more complete debridement than conventional treatment.
There is limited evidence on the healing effects of debridement devices.
Hydrocolloid dressing was associated with almost three-times more complete healing compared with saline gauze.
There is evidence that hydrogel and hydropolymer may be associated with 50% to 70% more complete healing of pressure ulcers than hydrocolloid dressing.
No statistically significant differences in complete healing were detected among other modern dressings.
There is evidence that polyurethane foam dressings and hydrocellular dressings are more absorbent and easier to remove than hydrocolloid dressings in ulcers with moderate to high exudates.
In deeper ulcers (stage III and IV), the use of alginate with hydrocolloid resulted in significantly greater reduction in the size of the ulcers compared to hydrocolloid alone.
Studies on sustained silver-releasing dressing demonstrated a tendency for reducing the risk of infection and promoting faster healing, but the sample sizes were too small for statistical analysis or for drawing conclusions.
Biological Therapies
The efficacy of platelet-derived growth factors (PDGFs), fibroblast growth factor, and granulocyte-macrophage colony stimulating factor in improving complete healing of chronic pressure ulcers has not been established.
Presently only Regranex, a recombinant PDGF, has been approved by Health Canada and only for treatment of diabetic ulcers in the lower extremities.
A March 2008 US Food and Drug Administration (FDA) communication reported increased deaths from cancers in people given three or more prescriptions for Regranex.
Limited low-quality evidence on skin matrix and engineered skin equivalent suggests a potential role for these products in healing refractory advanced chronic pressure ulcers, but the evidence is insufficient to draw a conclusion.
Adjunctive Physical Therapy
There is evidence that electrical stimulation may result in a significantly greater reduction in the surface area and more complete healing of stage II to IV ulcers compared with sham therapy. No conclusion on the efficacy of electrotherapy can be drawn because of significant statistical heterogeneity, small sample sizes, and methodological flaws.
The efficacy of other adjunctive physical therapies [electromagnetic therapy, low-level laser (LLL) therapy, ultrasound therapy, ultraviolet light therapy, and negative pressure therapy] in improving complete closure of pressure ulcers has not been established.
Nutrition Therapy
Supplementation with 15 grams of hydrolyzed protein 3 times daily did not affect complete healing but resulted in a 2-fold improvement in Pressure Ulcer Scale for Healing (PUSH) score compared with placebo.
Supplementation with 200 mg of zinc three times per day did not have any significant impact on the healing of pressure ulcers compared with a placebo.
Supplementation of 500 mg ascorbic acid twice daily was associated with a significantly greater decrease in the size of the ulcer compared with a placebo but did not have any significant impact on healing when compared with supplementation of 10 mg ascorbic acid three times daily.
A very high protein tube feeding (25% of energy as protein) resulted in a greater reduction in ulcer area in institutionalized tube-fed patients compared with a high protein tube feeding (16% of energy as protein).
Multinutrient supplements that contain zinc, arginine, and vitamin C were associated with a greater reduction in the area of the ulcers compared with standard hospital diet or to a standard supplement without zinc, arginine, or vitamin C.
Firm conclusions cannot be drawn because of methodological flaws and small sample sizes.
Multidisciplinary Wound Care Teams
The only RCT suggests that multidisciplinary wound care teams may significantly improve healing in the acute care setting in 8 weeks and may significantly shorten the length of hospitalization. However, since only an abstract is available, study biases cannot be assessed and no conclusions can be drawn on the quality of this evidence.
PMCID: PMC3377577  PMID: 23074533

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