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The use of platelet-rich fibrin (PRF) is investigated in ulcer management because it provides a healing milieu rich in growth factors and cytokines. Although crucial, the relevance of secondary dressings is under-researched and no data support the use of any particular dressing in preference to another. We assessed the properties of different dressing categories, including alginates, hydrocolloids, foams, hydrofibers, films, meshes and gauzes, in terms of affinity for PRF, releasate management (retention/extrusion) and the kinetics of cytokine release as well as the influence of each combination product, [PRF + dressing], on dermal cell behaviour, aiming to provide useful information for choosing the most adequate dressing for each particular patient. Active dressings including alginates, hydrofibers, foams and hydrocolloids blend with PRF, creating a diverse combination of products with different performances. Alginate and hydrofiber showed the highest affinity but moderate retention of releasate, without interfering with cell functions. Instead, the foam sequestered the releasate and hindered the release of growth factors, thereby compromising cell activities. Film and mesh presented very poor releasate retention and performed similarly to PRF by itself. Affinity index and releasate management explained 79% of platelet-derived growth factor (PDGF-BB) concentration variability, p < 0.001. Cell proliferation depended on the ability of the combination product to retain/release supernatant, PDGF-BB concentration and cell adhesion R 2 = 0.91, p = 0.014.

Medical interest in "blood-derived products for tissue repair/regeneration" has old roots, starting with chronic wounds in the 1980s, and boosted by sports medicine at the beginning of the millennium, when elite athletes treated with platelet rich plasma (PRP) resumed competition earlier than expected [...].

Current research on common musculoskeletal problems, including osteoarticular conditions, tendinopathies, and muscle injuries, focuses on regenerative translational medicine. Platelet-rich plasma therapies have emerged as a potential approach to enhance tissue repair and regeneration. Platelet-rich plasma application aims to provide supraphysiological concentrations of platelets and optionally leukocytes at injured/pathological tissues mimicking the initial stages of healing. However, the efficacy of platelet-rich plasma is controversial in chronic diseases because patients' outcomes show partial improvements. Platelet-rich plasma can be customized to specific conditions by selecting the most appropriate formulation and timing for application or by combining platelet-rich plasma with synergistic or complementary treatments. To achieve this goal, researchers should identify and enhance the main mechanisms of healing. In this review, the interactions between platelet-rich plasma and healing mechanisms were addressed and research opportunities for customized treatment modalities were outlined. The development of combinational platelet-rich plasma treatments that can be used safely and effectively to manipulate healing mechanisms would be valuable and would provide insights into the processes involved in physiological healing and pathological failure.

Background: Platelet-rich plasma therapies for tendinopathy appear to provide moderate pain reduction. However, the biological mechanisms behind the observed clinical effects remain poorly characterized., Questions/purposes: The purpose of this study was to explore whether platelet-rich plasma modifies the inflammatory/angiogenic status of already inflamed tenocytes by examining (1) gene expression; (2) modulation of chemokine and interleukin secretion; and (3) differences between healthy and tendinopathic tenocytes., Methods: Cells from both healthy and tendinopathic tendons were exposed to interleukin (IL)-1ß and after treated with platelet-rich plasma. Modifications in the expression of selected genes were assessed by real-time reverse transcription-polymerase chain reaction and changes in secretion of angiogenic/inflammatory molecules by enzyme-linked immunosorbent assay. Platelet-rich plasma-induced changes in tendinopathic cells were compared with normal after normalizing platelet-rich plasma data against IL-1ß status in each specific sample., Results: In IL-1ß-exposed cells, platelet-rich plasma downregulates expression of IL-6/CXCL-6 (mean, 0.015; 95% confidence interval [CI], 0.005-0.025; p = 0.026), IL-6R (mean, 0.61; 95% CI, 0.27-0.95; p = 0.029), and IL-8/CXCL-8 (mean, 0.02; 95% CI, 0.007-0.023; p = 0.026). Secretion of IL-6/CXCL6, 0.35 (95% CI, 0.3-0.4; p = 0.002), IL-8/CXCL8, 0.55 (95% CI, 0.5-0.7; p = 0.01), and monocyte chemoattractant protein-1/CCL2, 0.40 (95% CI, 0.2-0.6; p = 0.001) was reduced by platelet-rich plasma, whereas vascular endothelial growth factor increased by twofold, (95% CI, 1.7-2.3; p < 0.001). RANTES/CCL5 increased by10-fold (95% CI, 4-17) and hepatocyte growth factor by 21-fold (95% CI, 0.2-42) in tendinopathic and by 2.3-fold (95% CI, 2-3) and threefold (95% CI, 1-5) in normal cells (p = 0.005 for both)., Conclusions: Platelet-rich plasma induces an immunomodulatory and proangiogenic phenotype consistent with healing mechanisms with few differences between tendinopathic and normal cells., Clinical Relevance: Platelet-rich plasma injections in pathological and nearby tissue might help to recover tendon homeostasis.

Since the experimental conditions of cell cultures may bias results, it is critical to use suitable models. This is also true in the context of tendon cell biology and the study of platelet-rich plasma (PRP) therapies and PRP-augmented cell-based therapies. We compared the culture of human tendon cells in 2 dimensions (2D) with PRP-supplemented media to culture in matching 3-dimensional (3D) PRP hydrogels. Cell proliferation, cell shape, and the pattern of gene and protein expression were examined. Our data revealed modifications in cell shape and enhanced expression of tenomodulin and scleraxis in 3D hydrogels. Additionally, protein secretion analysis using glass-based arrays specific for angiogenesis revealed differences in interleukin (IL)-6 and IL-8 protein expression between 2D cultures and 3D hydrogels, while the secretion of other angiogenic or inflammatory cytokines was unaffected. Our study suggests that 3D hydrogels are physiologically more relevant than 2D cultures in the study of tendon cells, based on cell shape, support of tenocyte proliferation, phenotype, and the pattern of gene and protein expression., (© 2015 S. Karger AG, Basel.)

Background: Vascular ulcers are commonly seen in daily practice at all levels of care and have great impact at personal, professional and social levels with a high cost in terms of human and material resources. Given that the application of autologous platelet rich plasma has been shown to decrease healing times in various different studies in the hospital setting, we considered that it would be interesting to assess the efficacy and feasibility of this treatment in primary care. The objectives of this study are to assess the potential efficacy and safety of autologous platelet rich plasma for the treatment of venous ulcers compared to the conventional treatment (moist wound care) in primary care patients with chronic venous insufficiency (C, clinical class, E, aetiology, A, anatomy and P, pathophysiology classification C6)., Design: We will conduct a phase III, open-label, parallel-group, multicentre, randomized study. The subjects will be 150 patients aged between 40 and 100 years of age with an at least 2-month history of a vascular venous ulcer assigned to ten primary care centres. For the treatment with autologous platelet rich plasma, all the following tasks will be performed in the primary care setting: blood collection, centrifugation, separation of platelet rich plasma, activation of coagulation adding calcium chloride and application of the PRP topically after gelification. The control group will receive standard moist wound care. The outcome variables to be measured at baseline, and at weeks 5 and 9 later include: reduction in the ulcer area, Chronic Venous Insufficiency Quality of Life Questionnaire score, and percentage of patients who require wound care only once a week., Discussion: The results of this study will be useful to improve the protocol for using platelet rich plasma in chronic vascular ulcers and to favour wider use of this treatment in primary care., Trial Registration: Current Controlled Trials NCT02213952.

Introduction: At the beginning of the new millennium, there was a breakthrough in platelet-rich plasma (PRP) therapy for tissue repair. The mechanisms governing the effects of this therapy in joint pathology remain largely unexplored., Areas Covered: This review is primarily based on PubMed and Web of Knowledge searches with the terms osteoarthritis in combination with PRP, treatment, cartilage, synovium, platelets, inflammation and/or angiogenesis. This search was completed by a manual search for relevant studies. We mainly include papers from the last 5 years. The concept of dynamic reciprocity is used to shape understanding of the spatial relationship between cells and their microenvironments as well as between tissues within the joint. We describe the processes of joint injury and pathology relevant to the mechanism of action of PRP, and elaborate insights into how PRP components may influence inflammation, angiogenesis, cell death and cartilage chondroprotection., Expert Opinion: PRP therapies are more complicated than previously acknowledged, and an understanding of the fundamental processes and pivotal molecules involved will hopefully be elucidated soon. This challenge is to provide a comprehensive description of the relationship between PRP components, healing mechanisms and clinical outcomes. Although PRP therapies in clinical trials await assessment, they have shed light on new avenues of management because of their effects on repair functions.

Platelet-rich plasma (PRP) therapy is an emerging technology that aims to improve the process of tissue repair through local delivery of autologous bioactive agents to influence critical physiological mechanisms such as inflammation, angiogenesis, or extracellular matrix synthesis. These biological properties have prompted the therapeutic administration of PRP in orthopedics and sports medicine. Given its biocompatibility and healing properties, percutaneous injections of PRP are used in athletes to treat tendon and muscle injuries. Studies of varying levels of evidence have demonstrated the safety and beneficial effects of PRP in these applications, but standardization of the methods of plasma preparation and procedures for application is necessary for further advancements. Continued efforts to identify factors that influence the biological response to PRP treatment may yield new formulations tailored to each specific application. The growing emphasis on an evidence-based approach in the sports medicine setting demands additional research efforts before incorporating this technology in routine clinical care.

Importance of the Field: The therapeutic use of platelet-rich plasma (PRP) is an autologous biotechnology that relies on the local delivery of a wide range of growth factors and cytokines with the aim of enhancing tissue healing. Understanding both tendon healing and PRP therapies is an area of research that is critically important in developing optimal formulations and protocols to achieve the intended therapeutic effects., Areas Covered in This Review: We summarise recent information on the mechanisms inherent to the earliest response to tendon injury. We then describe the positive effect of PRP therapies on tendon healing. Research on tendinopathy has produced several biological hypotheses based on histopathological, biochemical and clinical findings showing that cell apoptosis, angiofibroblastic features or abnormal biochemical adaptations underlie the condition., What the Reader Will Gain: The article provides insights into early healing mechanisms and the influence of PRP therapies on inflammation, cell migration, angiogenesis and the proliferation and synthesis of extracellular matrix. The knowledge gained helps to better understand and optimize tendon therapies., Take Home Message: The use of endogenous therapies has a positive effect on experimental tendon healing. However, several obstacles need to be addressed to optimise medical practice in this field.

Platelets help prevent blood loss at sites of vascular injury. To do this, they adhere, aggregate and form a procoagulant surface favoring thrombin generation and fibrin formation. In addition, platelets express and release substances that promote tissue repair and influence processes such as angiogenesis, inflammation and the immune response. They contain large secretable pools of biologically active proteins, while newly synthesized active metabolites are also released. Although anucleate, activated platelets possess a spliceosome and can synthesize tissue factor and interleukin-1beta. The binding of secreted proteins within a developing fibrin mesh or to the extracellular matrix can create chemotactic gradients favoring the recruitment of stem cells, stimulating cell migration and differentiation, and promoting repair. The therapeutic use of platelets in a fibrin clot has a positive influence in clinical situations requiring rapid healing. Dental implant surgery, orthopaedic surgery, muscle and tendon repair, skin ulcers, hole repair in eye surgery and cardiac surgery are situations where the use of autologous platelets accelerates healing. We now review the ways in which platelets participate in these processes.

Autologous Preparation Rich in Growth Factors (PRGF), a small volume of plasma enriched in platelets, is a novel therapeutic strategy for the acceleration of the wound healing of a wide range of tissues because of the continuous release of multiple growth factors, including PDGF-AB, TGF-beta1, IGF-I, HGF, VEGF-A, and EGF. In this article, we have characterized the PRGF preparation and designed a randomized open-label controlled pilot trial to evaluate the effectiveness of PRGF in the treatment of chronic cutaneous ulcers. Results showed that at 8 weeks, the mean percentage of surface healed in the PRGF group was 72.94% +/- 22.25% whereas it was 21.48% +/- 33.56% in the control group (p < 0.05). These results, with the limitations of a pilot study, suggest that topical application of PRGF is more effective than standard therapy in helping a chronic ulcer to heal., ((c) 2007 Wiley Periodicals, Inc.)

Platelets are known for their role in haemostasis where they help prevent blood loss at sites of vascular injury. To do this, they adhere, aggregate and form a procoagulant surface leading to thrombin generation and fibrin formation. Platelets also release substances that promote tissue repair and influence the reactivity of vascular and other blood cells in angiogenesis and inflammation. They contain storage pools of growth factors including PDGF, TGF-beta?and VEGF as well as cytokines including proteins such as PF4 and CD40L. Chemokines and newly synthesised active metabolites are also released. The fact that platelets secrete growth factors and active metabolites means that their applied use can have a positive influence in clinical situations requiring rapid healing and tissue regeneration. Their administration in fibrin clot or fibrin glue provides an adhesive support that can confine secretion to a chosen site. Additionally,the presentation of growth factors attached to platelets and/or fibrin may result in enhanced activity over recombinant proteins. Dental implant surgery with guided bone regeneration is one situation where an autologous platelet-rich clot clearly accelerates ossification after tooth extraction and/or around titanium implants. The end result is both marked reductions in the time required for implant stabilisation and an improved success rate. Orthopaedic surgery, muscle and/or tendon repair, reversal of skin ulcers, hole repair in eye surgery and cosmetic surgery are other situations where autologous plate-lets accelerate healing. Our aim is to review these advances and discuss the ways in which platelets may provide such unexpected beneficial therapeutic effects.

Foot ulcer is a major complication of diabetes mellitus and often precedes leg amputation. Among the different methods to achieve ulcer healing, the use of platelet‐rich plasma, which is rich in multiple growth factors and cytokines and may have similarities to the natural wound healing process, is gaining in popularity. A systematic review with meta‐analyses was performed to evaluate the safety and clinical effectiveness of platelet‐rich plasma for the treatment of diabetic foot ulcers compared to standard treatment or any other alternative therapy. The electronic databases Medline, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials were consulted in March 2017 with no restrictions placed on the publication date. Predefined criteria were used to determine inclusion of studies and to assess their methodologic quality. Eight randomized clinical trials and two prospective longitudinal‐observational studies with control group were included. Platelet‐rich plasma treatment increased the likelihood of chronic wound healing (RR = 1.32; 95% CI: 1.11, 1.57, I2 = 15%) while the volume of the ulcer (MD = 0.12 cm2; 95% CI: 0.08, 0.16; p < 0.01; I2 = 0%) and time to complete wound healing (MD = −11.18 days; 95% CI: −20.69, −1.68; I2 = 53%) decreased. Regarding safety profile, platelet‐rich plasma did not differ from standard treatment in terms of probability of occurrence of wound complications (RR = 0.57; 95% CI: 0.25, 1.28; I2 = 0%) or recurrences (RR = 2.76; 95% CI: 0.23, 33.36; p = 0.43; I2 = 82%) but it decreased the rate of adverse events (RR = 0.80; 95% CI: 0.66, 0.96; p = 0.02; I2 = 0%). Cumulative meta‐analysis revealed that there is enough evidence to demonstrate a statistically significant benefit. However, studies included presented serious methodologic flaws. According to the results, platelet‐rich plasma could be considered a candidate treatment for nonhealing of diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

In patients with comorbidities, a large number of wounds become chronic, representing an overwhelming economic burden for healthcare systems. Engineering the microenvironment is a paramount trend to activate cells and burst-healing mechanisms. The extrusion bioprinting of advanced dressings was performed with novel composite bioinks made by blending adipose decellularized extracellular matrix with plasma and human dermal fibroblasts. Rheological and microstructural assessments of the composite hydrogels supported post-printing cell viability and proliferation over time. Embedded fibroblasts expressed steady concentrations of extracellular matrix proteins, including type 1, 3 and 4 collagens and fibronectin. ELISA assessments, multiplex protein arrays and ensuing bioinformatic analyses revealed paracrine activities corresponding to wound-healing activation through the modulation of inflammation and angiogenesis. The two modalities of advanced dressings, differing in platelet number, showed differences in the release of inflammatory and angiogenic cytokines, including interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conditioned media stimulated human-dermal-cell proliferation over time. Our findings open the door to engineering the microenvironment as a strategy to enhance healing. [ABSTRACT FROM AUTHOR]

Extrusion bioprinting based on the development of novel bioinks offers the possibility of manufacturing clinically useful tools for wound management. In this study, we show the rheological properties and printability outcomes of two advanced dressings based on platelet-rich plasma (PRP) and platelet-poor plasma (PPP) blended with alginate and loaded with dermal fibroblasts. Measurements taken at 1 h, 4 days, and 18 days showed that both the PRP- and PPP-based dressings retain plasma and platelet proteins, which led to the upregulation of angiogenic and immunomodulatory proteins by embedded fibroblasts (e.g., an up to 69-fold increase in vascular endothelial growth factor (VEGF), an up to 188-fold increase in monocyte chemotactic protein 1 (MCP-1), and an up to 456-fold increase in hepatocyte growth factor (HGF) 18 days after printing). Conditioned media harvested from both PRP and PPP constructs stimulated the proliferation of human umbilical vein endothelial cells (HUVECs), whereas only those from PRP dressings stimulated HUVEC migration, which correlated with the VEGF/MCP-1 and VEGF/HGF ratios. Similarly, the advanced dressings increased the level of interleukin-8 and led to a four-fold change in the level of extracellular matrix protein 1. These findings suggest that careful selection of plasma formulations to fabricate wound dressings can enable regulation of the molecular composition of the microenvironment, as well as paracrine interactions, thereby improving the clinical potential of dressings and providing the possibility to tailor each composition to specific wound types and healing stages. [ABSTRACT FROM AUTHOR]

The complex biology of platelets and their involvement in tissue repair and inflammation have inspired the development of platelet-rich plasma (PRP) therapies for a broad array of medical needs. However, clinical advances are hampered by the fact that PRP products, doses and treatment protocols are far from being standardized. Freeze-drying PRP (FD-PRP) preserves platelet function, cytokine concentration and functionality, and has been proposed as a consistent method for product standardization and fabrication of an off-the-shelf product with improved stability and readiness for future uses. Here, we present the current state of experimental and clinical FD-PRP research in the different medical areas in which PRP has potential to meet prevailing medical needs. A systematic search, according to PRISMA (Preferred Reported Items for Systematic Reviews and Meta-Analyses) guidelines, showed that research is mostly focused on wound healing, i.e., developing combination products for ulcer management. Injectable hydrogels are investigated for lumbar fusion and knee conditions. In dentistry, combination products permit slow kinetics of growth factor release and functionalized membranes for guided bone regeneration. [ABSTRACT FROM AUTHOR]