Epidemiology of adverse events.
\r\n\tIn the book the theory and practice of microwave heating are discussed. The intended scope covers the results of recent research related to the generation, transmission and reception of microwave energy, its application in the field of organic and inorganic chemistry, physics of plasma processes, industrial microwave drying and sintering, as well as in medicine for therapeutic effects on internal organs and tissues of the human body and microbiology. Both theoretical and experimental studies are anticipated.
\r\n\r\n\tThe book aims to be of interest not only for specialists in the field of theory and practice of microwave heating but also for readers of non-specialists in the field of microwave technology and those who want to study in general terms the problem of interaction of the electromagnetic field with objects of living and nonliving nature.
",isbn:"978-1-83968-227-8",printIsbn:"978-1-83968-226-1",pdfIsbn:"978-1-83968-228-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8f6a41e4f5ce0e9c48628516d7c92050",bookSignature:"Prof. Gennadiy Churyumov",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10089.jpg",keywords:"Electromagnetic Wave, Microwave Energy Application, Electromagnetic Energy Generation, Intelligent Microwave Heating, Microwave Organic Chemistry, Microwave Reactor, Microwave Discharge, Microwave Plasma, Microwave Drying System, Tissue Microwave Heating, Measurement Automation, Industrial Microwave Process",numberOfDownloads:224,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 3rd 2020",dateEndSecondStepPublish:"July 24th 2020",dateEndThirdStepPublish:"September 22nd 2020",dateEndFourthStepPublish:"December 11th 2020",dateEndFifthStepPublish:"February 9th 2021",remainingDaysToSecondStep:"7 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Prof. Gennadiy I. Churyumov is a professor at two universities: Kharkiv National University of Radio Electronics, and Harbin Institute of Technology and a senior IEEE member.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"216155",title:"Prof.",name:"Gennadiy",middleName:null,surname:"Churyumov",slug:"gennadiy-churyumov",fullName:"Gennadiy Churyumov",profilePictureURL:"https://mts.intechopen.com/storage/users/216155/images/system/216155.jfif",biography:"Gennadiy I. Churyumov (M’96–SM’00) received the Dipl.-Ing. degree in Electronics Engineering and his Ph.D. degree from the Kharkiv Institute of Radio Electronics, Kharkiv, Ukraine, in 1974 and 1981, respectively, as well as the D.Sc. degree from the Institute of Radio Physics and Electronics, National Academy of Sciences of Ukraine, Kharkiv, Ukraine, in 1997. \n\nHe is a professor at two universities: Kharkiv National University of Radio Electronics, and Harbin Institute of Technology. \n\nHe is currently the Head of a Microwave & Optoelectronics Lab at the Department of Electronics Engineering at the Kharkiv National University of Radio Electronics. \n\nHis general research interests lie in the area of 2-D and 3-D computer modeling of electron-wave processes in vacuum tubes (magnetrons and TWTs), simulation techniques of electromagnetic problems and nonlinear phenomena, as well as high-power microwaves, including electromagnetic compatibility and survivability. \n\nHis current activity concentrates on the practical aspects of the application of microwave technologies.",institutionString:"Kharkiv National University of Radio Electronics (NURE)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"24",title:"Technology",slug:"technology"}],chapters:[{id:"74623",title:"Influence of the Microwaves on the Sol-Gel Syntheses and on the Properties of the Resulting Oxide Nanostructures",slug:"influence-of-the-microwaves-on-the-sol-gel-syntheses-and-on-the-properties-of-the-resulting-oxide-na",totalDownloads:94,totalCrossrefCites:0,authors:[null]},{id:"75284",title:"Microwave-Assisted Extraction of Bioactive Compounds (Review)",slug:"microwave-assisted-extraction-of-bioactive-compounds-review",totalDownloads:12,totalCrossrefCites:0,authors:[null]},{id:"75087",title:"Experimental Investigation on the Effect of Microwave Heating on Rock Cracking and Their Mechanical Properties",slug:"experimental-investigation-on-the-effect-of-microwave-heating-on-rock-cracking-and-their-mechanical-",totalDownloads:28,totalCrossrefCites:0,authors:[null]},{id:"74338",title:"Microwave Synthesized Functional Dyes",slug:"microwave-synthesized-functional-dyes",totalDownloads:21,totalCrossrefCites:0,authors:[null]},{id:"74744",title:"Doping of Semiconductors at Nanoscale with Microwave Heating (Overview)",slug:"doping-of-semiconductors-at-nanoscale-with-microwave-heating-overview",totalDownloads:45,totalCrossrefCites:0,authors:[null]},{id:"74664",title:"Microwave-Assisted Solid Extraction from Natural Matrices",slug:"microwave-assisted-solid-extraction-from-natural-matrices",totalDownloads:25,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"60108",title:"Adverse Events in Hospitals: “Swiss Cheese” Versus the “Hierarchal Referral Model of Care and Clinical Futile Cycles”",doi:"10.5772/intechopen.75380",slug:"adverse-events-in-hospitals-swiss-cheese-versus-the-hierarchal-referral-model-of-care-and-clinical-f",body:'\nMrs. M, a fit 69-year-old, underwent an uncomplicated elective laparoscopic cholecystectomy [1]. The next morning (Day-1), upon review by the surgical team, it was decided that she should remain for overnight observation due to some shoulder tip pain and nausea. That afternoon, she was transferred without the consultation of the surgical team from the surgical ward to a low dependency rehabilitation unit. By the following morning (Day-2), she was tachycardic, diaphoretic and had a distended abdomen. The ward medical officer reviewed Mrs. M and prescribed intravenous (IV) fluids and analgesia, ordered blood tests, and requested an urgent surgical review. The surgical team then saw Mrs. M as part of their usual morning ward round, and she still had generalised abdominal tenderness and abnormal vital signs. An abdominal X-ray and CT scan were ordered.
\nMrs. M continued to deteriorate over the day. Another set of abnormal vital observations was taken sometime after the ward round, yet no doctor was informed. Mrs. M was seen by the two interns attached to the surgical unit. They were called to review her in the CT room due to concerning vital signs and contacted their registrar for assistance. They prescribed IV therapy and analgesia following their registrar’s phone advice.
\nUpon discussion of the CT results between the consultant and registrar midday, it was decided that Mrs. M was to return to theatre later that day for explorative laparotomy, and then to transfer to ICU for post-operative observation. Mrs. M was therefore assessed by the intensivist on-duty who diagnosed peritonitis and renal failure, and prescribed triple antibiotics and rapid IV fluid therapy, and strict monitoring of fluid balance. She was concurrently seen by the anaesthetist on-duty for pre-anaesthetic assessment. As Mrs. M had single IV access, only one antibiotic was administered by the time she was called to the operating room.
\nOnce in the operating theatre, surgery was delayed by an hour and ten minutes when Mrs. M becoming profoundly hypotensive upon anaesthetic induction. A bile leak was found intra-operatively and the abdomen lavaged. It was not discovered until her arrival in ICU later that evening that Mrs. M had only received one of the three prescribed antibiotics. By then, Mrs. M was severely septic, requiring inotropes, dialysis and mechanical ventilation. A second laparotomy, 2 days (Day-5) later found widespread bowel and hepatic ischaemia, and Mrs. M died the next day of multi-organ failure (Day-6).
\nThe death of Mrs. M, a fit 69-year-old lady, who underwent an elective procedure, is a classic case of clinical futile cycles (CFC) [1, 2, 3]. This term has been borrowed from biochemistry where two (or more) always on enzymatic systems change one chemical to another and then back to the original chemical with no net output but the use of much energy. In Mrs. M’s case, there was certainly a lot of clinical activity from all levels of the medical and nursing hierarchy; yet, the net outcome was a preventable death. The ward doctor on day 2 did all the right things, IV fluids, ordered labs, and requested an urgent surgical review. The surgical team certainly had this patient on the radar, performed a CT scan, and got the theatre organised and the post op ICU bed. The surgical registrar gave good instructions over the phone and the consultant agreed with all of the above and undertook the re-operations.
\nHowever, if we ‘scratch the surface’ a bit more in this case sadly, Mrs. M found herself in the midst of an unintended CFC:
nurses, doing the right thing, taking the observations and notifying the medical staff,
interns with little knowledge and even less experience (too much time at med school learning ALS and CPR, but not enough time with real sick patients) of acutely deteriorating patients and certainly not enough emotional intelligence to manage all the players in a clinical scenario like Mrs. M’s,
a surgical registrar who would have all the competencies, but is too busy to attend the patient and direct the care at the bedside and instead delegates tasks to the interns above by phone and
a consultant surgeon with the skill and ability to fix the problem but most commonly employed only on a sessional basis, so often not actually there in the hospital in question.
So, at four levels above in the traditional hierarchal referral model of care, everyone is doing the right thing. CFC is the explanation for all this activity, whilst appropriate for the individual practitioner concerned was not sufficient to get Mrs. M to theatre more urgently to have the problem fixed. In addition to the CFC, we have become accustomed to the naïve expectation that some sort of track and trigger system (Medical Emergency Team, Rapid Response System) will fix the problem by getting the patients deterioration alerted. However, that is all they do. The rest is up to the clinicians on the ground to make the right diagnosis, determine the level of severity of the condition, initiate management, notify the right people and with all pressures of the job to do this in a timely fashion to prevent patient catastrophe [4, 5]. All too often, it is only patient physiological reserve that defends patients from a system of care that is designed to fail them.
\nThe first chapter in this series of Patient Safety Vignettes [6] gives an overview of adverse events in health care and provides a standardised glossary of the various definitions that are used. An adverse event is defined as an injury resulting from a patient’s medical management rather than a consequence of the patient’s underlying medical condition or conditions [6, 7, 8, 9, 10]. Adverse events are common and costly to both the affected patients and the health-care system [6, 11, 12, 13, 14, 15, 16, 17, 18]. In the last two decades, the incidence, aetiology and outcomes from adverse events have been documented mostly in the hospital setting [6, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]. Taking these studies together, approximately 10% of hospital patient admissions have some sort of adverse event. Of these, half result in no long-term harm to the patient. However, 10% (of the 10%, i.e., 1% of all hospital admissions) of the affected patients suffer significant harm such that they either die of or are left with some sort of permanent disability as a result of the adverse event (Table 1) [37]. In 1995, the cost of adverse events to the Australian health-care system was estimated at $2 (AUD) billion dollars [8]. Attempts to reduce the incidence of adverse events and make hospitals safer have been largely unsuccessful [38, 39, 40, 41]. Like other diseases and conditions, an understanding of the underlying aetiology or ‘pathophysiology’ of adverse events is important for the development of preventative strategies. To date, the predominant theory to explain adverse events in health has been the ‘Swiss Cheese’ model developed by James Reason from his analysis of large-scale industrial and organisational accidents [42]. In this chapter, we examine the theory and, in particular, its limitations when applied to hospital systems, with specific reference, to the ‘deteriorating patient’, the final common pathway for most adverse events when patients suffer harm. We then propose an alternative called CFC within the traditional hierarchical referral system of care, to explain hospital setting adverse events which takes into account some of the unique cultural systems that exist in health care, but in hospitals in particular [43, 44]. Finally using this model, we then propose some fundamental reforms for the prevention of these adverse events in hospitals.
\nStudy (year of study) | \nMethodology | \nSetting | \nSample | \nIncidence (%) | \nOutcome death | \nOutcome permanent disability | \nPreventability | \nNegligent care | \nCost (annual) | \n
---|---|---|---|---|---|---|---|---|---|
California medical association (1977) [24] | \nRandom sample retrospective case note review | \n\n | \n | 4.2 | \nN/A | \nN/A | \nN/A | \n19.1% | \n\n |
Harvard medical practice study (1991) [25, 26] | \nTwo-stage random sample retrospective case note review | \n51 acute-care New York State hospitals | \n30,121 | \n3.7 | \n13.6% | \n2.6% | \n58% | \nN/A | \nN/A | \n
Utah and Colorado study (1992) [27] | \nRandom sample retrospective case note review | \n28 general hospitals | \n15,000 | \n2.9 | \n6.6% | \n8.5% | \n53% | \n30% | \n\n |
Quality in Australian Health Care Study (1992) [28] | \nTwo-stage random sample retrospective case note review | \n28 acute-care hospitals of different sizes in 2 Australian states | \n14,179 | \n16.6 | \n4.9% | \n8.9% | \n51% | \nN/A | \n$2 billion (AUD) | \n
New Zealand public hospitals (1998) [29] | \nTwo-stage random sample retrospective case note review | \n13 general acute hospitals | \n6579 | \n11.2 | \n15% for both categories | \n\n | N/A | \nN/A | \n\n |
United Kingdom (1999) [30] | \nRandom sample retrospective case note review | \n2 acute-care London hospitals | \n1014 | \n11.7 | \n8.2% | \n6.3% | \nN/A | \nN/A | \n\n |
Canadian health care study (2000) [31] | \nTwo-stage random sample retrospective case note review | \n1 teaching, 1 large community and 2 small community hospitals | \n3745 | \n7.5 | \n20% for both categories | \n\n | 36.9% | \nN/A | \n\n |
Brazilian hospitals (2003) [32] | \nRandom sample retrospective case note review | \n3 teaching hospitals in Rio de Janeiro | \n1103 | \n7.6 | \nN/A | \nN/A | \n66.7% | \nN/A | \n\n |
Dutch hospitals (2004) [33] | \nThree-stage random sample retrospective case note review | \n21 acute-care hospitals | \n7426 | \n5.7 | \n12.8% for both categories | \n\n | 40.3% | \nN/A | \n\n |
Italian acute care hospitals (2008) [34] | \nTwo-stage random sample retrospective case note review | \n1 acute-care hospital | \n1501 | \n3.3 | \n\n | \n | \n | \n | \n |
Portuguese hospitals (2009) [35] | \nTwo-stage random sample retrospective case note review | \n3 acute-care hospitals in Lisbon | \n1669 | \n11.1 | \n10.8% | \n\n | 53.2% | \n\n | Euro 470,380 Direct costs | \n
Swedish Hospitals (2009) [36] | \nThree-stage random sample retrospective case note review | \n28 acute-care hospitals | \n1967 | \n12.3 | \n3.0% | \n9.0% | \n70% | \nN/A | \n63,0000 hospital bed days | \n
Epidemiology of adverse events.
James Reason in his book ‘Managing the Risks of Organizational Accidents’ states that organisational accidents, as opposed to individual accidents, are predictable events [42]. An individual accident is one in which a person or a group of people makes an individual slip, lapse or error of judgement with the net result being an adverse outcome either to the person or the people who erred, or to the person or people in the immediate vicinity. As such, there is usually a relatively tight, simple explanation for cause and effect in an individual accident. On the other hand, organisational accidents have ‘multiple causes involving many people at different levels of an organization’ [42]. These events, whilst usually infrequent, are often catastrophic. Analyses of such organisational accidents often reveal that the defences an organisation has to prevent such catastrophes are breached by a unique series of sequential hazards that play out in an environment of latent conditions, the so-called ‘Swiss Cheese’. It follows that one can decrease the incidence of these organisational accidents by increasing the number of defences (more cheese slices) and/or by shrinking the size of the holes in each of the defences (Figure 1).
\nThe reason ‘Swiss cheese’ model [37] (with kind permission from Ashgate Publishing).
In 2008, Palmieri et al. published their ‘Health Care Error Proliferation Model’ of adverse health-care events [45]. This model takes the ‘Swiss Cheese Model’ and specifically adapts the various factors that exist in health care. Most notably, they place clinician vigilance as a key defence at the sharp end of the actual adverse event, in the form of clinical improvisation and localised workarounds. This clinician vigilance repairs gaps produced by actions, changes and adjustments that are made at the blunt end of the health-care organisation with its administrative and therefore higher level, layers of defence. A good example of this is the use of high-definition mobile telephone devices in rural and regional settings that allow almost an immediate transfer of clinical information to an appropriate clinician at a referral centre. However, this clinical workaround and improvisation is clearly at odds with most organisations’ patient privacy policies that have been developed at the blunt administrative end of the organisation.
\nHaving for the most part accepted the Reason ‘Swiss Cheese’ model of adverse events and adapted variations, most hospitals’ response to adverse events has been to increase defences at the blunt end of the health-care organisation’s administration [46]. These defences, in the hospital, take the form of dedicated quality and safety units and committees, electronic event-reporting systems and the development of appropriate standards linked to hospital accreditation [46]. The aim of each of these blunt end defence layers is to continually decrease the size of the holes in each defence layer, by more audits, meetings and root cause analysis projects combined with the use of the quality improvement cycle. Inevitably, what are generated are recommendations, guidelines and more policy and procedure.
\nThe ‘Swiss Cheese’ model does explain well some types of hospital adverse events, in particular patient falls, wrong-side surgery and medication errors. In the case of medication errors, the root cause analysis of these events often highlights holes in the ‘Swiss Cheese’, such as poor transcription of medication prescriptions and failure to do appropriate checks [47]. In the case of patient falls, there is failure to identify the ‘at risk’ patient and put appropriate preventative strategies in place. Fixing the holes or at least reducing the size of them can reduce the incidence of patient falls and medication errors. This can be done by and large with top-down policy and procedure and ensuring implementation of such [47]. The best example of this has been the reduction in the incidence of wrong-side surgery, with the implementation of time-out, with completion of a check list before surgery [48]. The Reason ‘Swiss Cheese’ model gives good explanation of the adverse event when there is a relatively tight temporal relationship, between the adverse event and the preventative strategies. The adverse event in these circumstances is itself evidence that a mistake or error was made. There is usually a series of clear errors with the ‘Swiss Cheese’ model that can be identified. This model then allows for preventative strategies to be implemented, and with the increasing move back to professional responsibility for compliance, in theory, at least the Holy Grail of the perfectly safe hospital should be attainable.
\nHowever, most adverse events in hospital, particularly the more serious ones, often do not have such clear errors with a tight temporal relationship with the adverse event and the contributing errors. When the temporal relationship between the adverse event and the preventative strategies is not so tight, hospital cultural factors start to be more significant, and the potential for policy and procedure to help is much less so, simply because it can be and often is ignored.
\nThere are three fundamental problems with the application of the ‘Swiss Cheese’ model to adverse events in hospitals. First, in the hospital, the distinction between individual and organisational accidents is not clear. The entire premise of the ‘Swiss Cheese’ model was the investigation of causation factors of large industrial accidents as opposed to individual accidents. In the hospital, we do not have large-scale accidents but, instead, multiple little accidents or adverse events daily, if not hourly, and in almost every setting. The study on the causation of adverse events in hospitals overwhelmingly points to failures at the sharp end of care delivery to the patient by frontline staff. Analysis of the causative factors associated with the adverse events in The Quality in Australian Health Care Study found that cognitive failure was a factor in 57% of these adverse events [49]. In this analysis, cognitive failure included such errors as failure to synthesise, decide and act on available information; failure to request or arrange an investigation, procedure or consultation; lack of care or attention; failure to attend; misapplication of, or failure to apply, a rule, or use of a bad or inadequate rule [49]. In a two-hospital study from the United Kingdom that looked at 100 sequential admissions to the intensive care unit (ICU) from ward areas, it was found that 54 had sub-optimal care on the ward prior to transfer [50]. This group of patients had a mortality rate of 56%. Some of the sub-optimal treatment factors included failure to seek advice, lack of knowledge, failure to appreciate clinical urgency and lack of supervision [50].
\nThe adoption of the Reason ‘Swiss Cheese’ model for organisational accidents has led the whole Quality and Safety industry, and in particular hospitals, looking for system solutions to what can be explained by individual competency and micro-environment cultural issues at the patient interface. In particular, a major rationale of Reason’s philosophy is to avoid individual accountability for errors and the culture of blame and shame. Nearly 20 years ago, Reason himself noted the folly of this approach in medicine when he stated, ‘It is curious that such a bastion of discretionary action as medicine should be moving towards a ‘Feed Forward’ mode of control when many other hitherto rule dominated domains – notably railways and oil exploration and production – are shifting towards performance-based controls and away from prescriptive ones’ [42]. When Reason talks about human contribution to organisational accidents, he describes two schemas of control [42]. A ‘Feed Forward’ control system is one where human performance is determined by rules and procedures as determined by an organisational standards and objectives (Figure 2). In this schema, occasional accidents and incidents are analysed and then fed back into either an alteration of an existing rule or a procedure or the creation of a new one. At the other end of the control spectrum, there is the model where organisational output is largely determined by individual human performance (Figure 3). The basis for this model is that, in the first instance, the humans are generally highly trained and that performance is controlled by continual performance reinforcement against a known or a standard comparator. The best example of this, in hospitals, is specialist medical practice. To even start specialist training, there have been many years of training and experience (medical school, house officer jobs and pre-specialty registrar placements) followed by a period of mentoring and in essence apprenticeship to learn the specialty to the known standard of the comparator, the standard of practice as maintained by the specialty colleges. Taking these two schemas, one can immediately see the trouble with health care in hospitals. It is a large industry with community and political expectations that are more congruent with the ‘Feed Forward’ schema, but yet with most of the actual clinical activity being undertaken by the ‘Human Performance’ schema.
\nThe reason ‘feedforward’ process control system [37] (with kind permission from Ashgate Publishing).
The reason feedback process control system [37] (with kind permission from Ashgate Publishing).
Thus, what we have seen in the construction of hospital adverse event defences is an over-reliance on the administrative blunt end of the organisation, in terms of policy and procedures, with the assumption that the health-care professionals at the patient end are competent and will be compliant. The shift to looking for hospital-wide problems has come at the cost of avoiding the issue of individual professional accountability and associated issues, most notably the education and certification of health-care professionals. In Australia and the United Kingdom, several studies indicate that the medical undergraduate syllabus does not provide graduates with the basic knowledge, skills and judgement to manage acute life-threatening emergencies [51, 52, 53]. These studies identified deficiencies in cognitive abilities, procedural skills and communication. Despite this, undergraduate and postgraduate curricula have been slow to embrace a patient safety culture [54, 55, 56].
\nThe second fundamental problem with the ‘Swiss Cheese’ model and the Palmieri variation of this are that they are overly simplistic and do not take into account the complexity of the patient and the hospital system. When a patient enters a hospital system, they enter a system where they will be exposed to a variety of hazards which, in turn, have numerous defences in place to prevent an adverse patient outcome. Operations, anaesthesia, medical interventions and procedures, drugs and fluids and even oxygen therapy constitute the hazards. Most defences in health care are reliant on the competence of the health-care professional and as such are ‘soft’. ‘Hard’ defences are those that are impossible to overcome, for example in anaesthesia where the administration of hypoxic gas mixtures is physically prevented. The soft defences, in health care, include treatment policies and procedures, manual alarm systems, and ad hoc hierarchical and lateral human checking systems. Soft defences are very reliant on the training and education that health-care workers receive and the culture of compliance. Superimposed on these layers of hazards and defences that confront a patient, there are the latent conditions that exist, most obviously within the patient, but more insidiously within the hospital as an organisation. A patient’s past medical history, family history, social history, associated co-morbidities, drug regimen and allergies largely constitute their latent conditions. These conditions and their relation to the current presenting complaint that brings the patient into the hospital system are territory that individual health-care workers are usually extremely well trained in and familiar with. Hospital latent conditions are not so explicit, particularly to the patient or the frontline health-care worker. They are made up of a complex matrix of production and cultural imperatives such as the financial operating environment, political and societal imperatives, medico-legal and insurance concerns, compliance issues imposed by various regulatory bodies (often with associated financial incentives or disincentives) and workforce and work-practice issues. Thus, in the hospital system, unlike any other industry, we have a high degree of ever-changing complexity, complex patients and a complex system where adverse events are essentially prevented by a whole host of predominantly soft defences [57]. The ‘Swiss Cheese’ model is a static model with fixed defences in terms of the layers and the size of holes in each layer. This translates well into most industries, but in health care, the complexity is dynamic and ever changing, the number of holes and layers change with every patient and each and every different health-care professional.
\nThe third problem with the ‘Swiss Cheese’ model is that adverse events in hospitals occur so insidiously that they become normalised into the operating behaviour and practice of the organisation. This is distinct from large-scale industrial accidents, where the impact of the event has a high degree of face validity, primarily due to the immediacy and scale of the event. Therefore, in terms of numbers, patient adverse events may constitute a crisis. However, to the individual practitioner or even hospital, these events may not appear to be a problem. On the whole, such events are infrequent and occur over a long time frame. For example, The Quality in Australian Health Care Study looked at a random sample of 14,179 admissions to 28 hospitals in two states of Australia in 1992 and documented 112 deaths (0.79%) and 109 cases where the adverse event caused greater than 50% disability (0.77%) [14]. Seventy per cent of the deaths and 58% of the cases of significant disability were considered to have had a high degree of preventability [49]. Thus, for the individual clinicians, treating departments and units, and even the 28 study hospitals themselves, their actual experience of these outcomes over the year would be minimal (one or two cases) [14].
\nThe ‘Swiss Cheese’ model gives a poor explanation of the multitude of insidious individual accidents that occur in hospitals and is too simplistic for the complexity of most patients and the complex matrix of health care that is provided in a hospital. Most importantly, the focus on system issues whilst valid and important has detracted from what is really needed: focussed attention on clinical competence and accountability at the patient interface.
\nThe term ‘Futile Cycle’ is a term used in cell biology and biochemistry to explain the conversion of one substance to another and back to the original substance by two always on enzymatic pathways. However, despite the enzymatic activity and energy utilisation, there is no net output or gain from this energy-consuming and active process. This is exactly what we see with hospital patient adverse events and in particular the deteriorating patient, a lot of clinical activity, none of which effectively alters the trajectory of the patient towards the adverse event. The clinical activity occurs in a traditional hierarchal referral model of care that by its very nature is often either unresponsive or slowly responsive and where the exhaustive policy and procedures are often ignored.
\nIn the hospital, the CFC usually starts with the most junior level of the ‘traditional hierarchical referral model of care’, at the bedside with the interaction between the junior nurse and the patient (Figure 4). With a clinical abnormality, be it an observation, a wrong drug order or a procedural failure, the junior nurse must make a decision as to the significance of the abnormality and the importance of reporting it to a more senior team member, either a senior nurse or the most available (usually junior) doctor. However, that decision to escalate the issue can be influenced in the workplace culture that exists in the particular micro-environment of that bedside and that ward at that time [58]. If the concern or abnormality is escalated, it is to the next person in the care hierarchy of the team looking after that patient. This is often the junior doctor who then needs to attend, assess and then also make a decision about whether or not to escalate the issue to the next person in the hierarchy. This is important because, for the most, the junior doctor does not have the skills or emotional intelligence to appropriately manage many of these clinical abnormalities [51, 52, 53, 54]. If the issue is escalated, it is often to a middle-grade doctor, one who is often a specialist in training and who as such may be difficult to find. Unlike their juniors, usually this grade of doctor does have the technical and clinical abilities to deal with the particular issue. However, they are often over-committed with clinics, operating theatre, but more importantly often see themselves more like the consultants they aspire to be rather than a junior doctor having to deal with patient problems on the ward. In addition, this grade of doctor is diagnosis–focused and often we see them giving instructions to their juniors (usually appropriately) to organise specialised investigations and other speciality consultations. There is nothing wrong with this, except for the fact that it is time-consuming [59].
\nClinical futile cycles [38, 39].
In support of the CFC model is the study that has looked at the causation of adverse events in hospitals [13, 37, 49, 50]. All these studies can assign almost all causation to three human factor issues at the patient interface: competency, cognition (or failure thereof) and culture. Perhaps, the most disturbing example of this was described in the MERIT study, a randomised cluster control study of Medical Emergency Teams (MET) [60] in 23 Australian hospitals (including private and rural hospitals) in 2002. In the nearly 500 cardiac arrests that occurred during the study, in more than a third of instances staff took abnormal (that broached MET activation criteria) patient observations in the 15 min prior to the cardiac arrest, but did not activate an emergency response. The first thing of note with this phenomenon was that the incidence of not calling for help in an abnormal patient situation was high at 30% in the intervention hospitals and 40% in the control hospitals. Put in another way, in the average Australian hospital in 2002, if a patient had documented abnormal signs, in the 15 min before a cardiac arrest, in up to 40% of the time the staff did nothing about this. Another thing of note with these findings is that in intervention hospitals that had an intense education process on the new MET activation policy and procedure, the incidence of calling for help was only 10% greater than the control hospitals [60]. It is here at the bedside with the pre-cardiac arrest patient that the staff are trapped in a CFC, unable to get out of it due to either clinical incompetency (not able to recognise and act for the pre-arrest patient) and/or culture, whereby calling for help maybe considered not the norm in that ward, on that shift at that time [4, 5, 61, 62, 63, 64].
\nThe ‘Swiss Cheese’ response when RRS fails at the sharp end, for whatever reason, the response is to assume policy and procedure failure, despite the fact that there is no direct evidence for the benefit of Rapid Response Systems (RRS) [62, 63, 64]. However, it is well documented that there may be problem with the face validity of RRS due to the very low specificity of the activation criteria [65, 66, 67]. Furthermore, there may be problems around staff competency or cultural issues around staff losing face by calling for help. As a result, rather than trying to understand or deal with this very real issue of face validity, possible competency issues and probable cultural issues, the administrative response, all too often, is just to alter the policy and procedure and make the activation criteria mandatory for the bedside staff [68].
\nIf we accept the model of CFC, it becomes immediately apparent that no amount of activity away from the sharp end of the health-care adverse event will help, least of all the generation of a more policy and procedure. Instead, we need to focus attention on the health-care professional and the immediate socio-cultural environment in which they work [69].
\nDealing first with the health-care worker, the selection of these individuals to undertake their chosen vocation is invariably done by consideration of various personal attributes, in the case of medicine academic achievement and individual performance in tests [69, 70, 71, 72, 73]. This process and subsequent education takes no account of the fact that as soon as these people graduate, they will be working in a team environment.
\nThe clinical care we deliver (and receive) is a function of the education and capability of our students who will eventually be our doctors and ultimately clinical leaders and decision-makers. What we teach and practise best is the point-of-care medicine and clinical interventions. Therefore, it is no surprise that what we examine and what students focus on are specific point-of-care clinical assessments and interventions [74]. This is best represented by the objective, structured, clinical, examination system (OSCE) that is now a widespread and common form of summative assessment [75]. In the OSCE, candidates undertake clinical assessment tasks at a number of specific stations for 5–8 min. Each station has a structured ‘score card’ that students must address to get the points. This system of examination in no way gives any indication on a student’s ability and competency to comprehensively take a history, perform a physical examination, synthesise these findings into a meaningful problem list and finally and actually least importantly come up with a diagnosis [76]. It has got to the point now in the undergraduate curriculum that the clinical process of whole patient assessment is variably taught and certainly not examined, in a sufficiently stringent manner to motivate students to spend long hours doing patient histories and examinations. Having competent health-care professionals spend time with and understanding our patients is the single biggest step to making health care safe.
\nSecond, priority needs to be given to the core business of hospital care, the interaction at the bedside and clinic between the patient and the various health-care professionals [4, 5, 61]. Clinical futile cycles give a practical platform to understand this culture. We need to accept that an abnormal or an inappropriate workplace culture is at the heart of every major inquiry into poor hospital care [77, 78, 79, 80, 81, 82]. Every report into these enquiries recommends change. Yet, 30 years on from Bristol [81], we have mid-Staffordshire [80]. So, what have we really learned from the reports and thousands of pages of recommendations? Nothing. We need a different strategy: one that puts the patient and their well-being first. This should be followed by the implicit understanding that our core business is that of interaction with the patient from the most basic and junior levels. The bedside health-care team needs to be trained, credentialed and supported to deliver better health care, not as individual players, but as members of a team.
\nDespite the hundreds of millions of dollars spent on patient safety, we have very little to show for it except the fact that we know that the problem is real, common and universal to all health-care settings. In this chapter, we propose that the reason why we have not been able to improve patient safety is because we really do not understand what is going on at the point of clinical intervention.
\nThe organisational response is based on mandated requirements, which look at system and operational issues. Rarely do we focus on the quality of the judgements made by the individual clinicians involved in adverse events and usually never do we question the clinical culture in which these events occur.
\nCFC provides an alternative framework to help understand adverse events and patient safety breaches, by forcing us to ask the question, ‘they or she/he, knew that there was a problem, or that there might be a problem, why didn’t they do something about it?’ The question needs to be put to all the involved clinicians regardless of where they sit in the traditional clinical hierarchy. The answer to the question will usually fall into one of three broad categories, first those involved simply did not know what was going on, second, they did know what was going on and they tried to do something about it, and third they did know that there was a problem and for whatever reason did nothing. The answer to this one question then allows for appropriate interventions at the health-care workplace. If the involved individuals were simply oblivious to the situation, then retraining, re-credentialing and recertification are required for those clinicians. If the problem was recognised and attempts made to ameliorate it, then the more traditional root cause analysis should shed light on the issues that need resolution. Lastly, if the problem was recognised and nothing done, then cultural issues are at play. These may range from the obvious (e.g., an overall culture of not calling senior clinicians at night about problems) to more serious issues of workplace bullying and harassment (e.g., senior clinicians when called overnight about problems, being rude, belittling the caller, blaming and side-stepping the problem to avoid coming in after hours).
\nCFC also provides us with a term or a condition that describes the ‘brain freeze’ state of mind that can occur in stressful clinical situations. For the individual clinician, recognising and knowing that they have a moment of ‘brain freeze’ and that they are stuck in a CFC is the first step to getting out of that situation. The best way out is quite simply to ask for help, or to take time-out to reassess the problem.
\nIn summary, we need to divert some of those hundreds of millions of dollars, away from committees, the quality and safety units, organisational and government mandatory-reporting systems back to understanding the core business of health care, the intervention between clinician and patient. Perhaps, then we will get the significant cultural change that needs to occur (and has occurred in other industries) that puts the saying ‘first do no harm’ at the centre of all clinical interactions.
\nDespite joint degeneration, caused mainly by osteoarthritis (OA), not being a threat to life, it meets conditions that make it a real problem for both patients and health systems. This pathology is one of the leading causes of disability in the middle-aged and elderly population, and although any joint can be affected, the hip and knee are the most affected ones. This high prevalence, with 250 million people with knee OA throughout the world, represents up to 2.5% of gross domestic product for developed countries [1]. In the coming years, prevalence and costs will increase because the risk factors that favor OA are inherent to today’s society such as the aging of the population, overweight, or an uncontrolled sports practice, both by excess and by default.
Patients with OA are characterized by pain, stiffness, and limitation of function, becoming disabling in the most advanced stages [2]. Initial conservative treatments include physiotherapeutic work, nutritional supplements, and oral administration of analgesic and anti-inflammatories. In the next phases, patients can be treated with intra-articular injections of hyaluronic acid. Regardless of the success of these treatments, all of them focus on symptomatic relief without stopping or slowing the progression of the disease, and the only solution for patients with the most severe degrees of OA is total knee arthroplasty [3]. This surgical intervention not only entails the risks derived from surgery, which may be unacceptable by some patients, but also involves the majority of the cost of health systems [4, 5]. Therefore, it is necessary to develop new therapies that improve the current ones in order not only to alleviate the symptoms but also to modify the course of the pathology to slow its progression or even reverse it. This would improve the quality of life of patients, delaying or avoiding a large number of surgical interventions as well as the expense they entail.
These therapies must be based on two main pillars that sustain a new approach in joint degeneration: first, treatments based on regenerative medicine which can act on tissue biology and modify the pathophysiology of OA such as gene therapy, Platelet-Rich Plasma (PRP), or mesenchymal stem cells (MSCs). Among these treatments, PRP is currently the most widely used due to its greater ease of regulating, obtaining, and applying as well as its low cost [6, 7]. However, it is necessary to deepen their knowledge and standardize products and protocols to optimize clinical results. The second cornerstone is to understand the joint as a whole organ, taking into consideration all its elements [8]. Knowing the relationships between the different tissues that form and define the joint is key for the correct application of treatments and address degenerative pathology completely. Thus, this chapter is intended to explain the role of PRP in joint degeneration, highlighting the therapeutic potential of PRP in all the components of the joint and its clinical translation.
All joint structures present a unique molecular and cellular composition as well as specific biomechanical properties; consequently, each element of the joint performs characteristic functions. However, they are all coordinated and related to create the biological machinery that allows the joint to have dynamic stability (Figure 1) [9]. This gives the joint a great adaptability to maintain a mechanical and biological balance, supporting and confronting physical forces or physiologic disorders. In a short look at the components of the joint, the periarticular muscles appear in the outermost section. This tissue presents vascular irrigation, many neuronal terminals, and high plasticity. The configuration of its extracellular matrix in a network of muscle fibers provides muscle elasticity and allows the mechanical forces generated by the muscle cells to be transmitted to the tendons, which will translate them into joint mobility [10]. However, its stability capacity is even more important than mobility in order to maintain joint homeostasis, the quadriceps muscle being key in knee anteroposterior steadiness. In addition, muscle tissue is essential in shock-absorbing, and together with the subchondral bone and ligaments, it accounts for 30–50% of the total absorbing energy [11]. Ligament composition is characterized by a high-water content and an extracellular matrix with a small number of fibroblasts. Collagen is the most predominant protein, mainly organized in type I collagen fibers that adopt many directions and orientations due to several forces these structures are subjected to [12]. Apart from their stabilizing function due to their biomechanical and viscoelastic properties, they are also responsible for detecting and controlling the position and movement of the knee. In this way, the joint has a balanced biomechanical behavior that prevents the origin of mechanical problems that lead to degeneration. The meniscus plays a fundamental role in functions of mechanical nature such as stability and shock-absorbing. It is a fibrocartilaginous tissue with an abundant extracellular matrix where cells such as fibroblasts and fibrochondrocytes are dispersed and where type I collagen is the predominant molecule. The presence of vascularization and nerve terminals is limited to the external zone or meniscal wall. These intra-articular elements located between the femoral condyles and the tibial plateau help stabilize the joint and withstand compression and sharing forces. In addition, they participate in the lubrication of the joint with the synovial membrane or synovium [13].
Joint as an organ. All the elements of the joint participate in its correct function and in the maintenance of the homeostasis. Although they all contribute to mechanical and biological stabilization, ligament and meniscus muscles play a mainly mechanical role, whereas the synovium, cartilage, and subchondral bone have a more biological action. Correct mechanical adaptation and a favorable biological environment allow the cells to maintain a gene expression that promotes the optimal maintenance of the extracellular matrix.
The synovium, together with the cartilage and subchondral bone, forms an important biological triangle to maintain homeostasis of the knee. Both nerve fibers and blood vessels are abundant in the synovium, which provides nutrients not only to this structure but also to the adjacent avascular cartilage. Its cellular composition stands out mainly for synoviocytes (macrophagic cells or type A and fibroblast-like cells or type B), although immune system cells and even MSCs are also present, the synovium being a source of stem cells of increasing interest [14]. Its main function is the production of synovial fluid, which is produced by type B synoviocytes. It soaks the intra-articular space and structures, being essential in the lubrication of the joint due to its hyaluronic acid and lubricin content. The synovial fluid is also an important source of nutrients, biomolecules, and cellular signals, so it is essential for the biological balance of the joint [15]. The second element of this biological triangle is the hyaline articular cartilage. It has a very low coefficient of friction that resists compression and shear forces and absorbs only 1–3% of the total energy. The main cellular element of this tissue is a low population of chondrocytes that is distributed along the extracellular matrix composed principally of type 2 collagen, in addition to other molecules such as proteoglycans or aggrecans. Its functions of lubrication and transmission of mechanical forces are performed thanks to a stratified tissue in different zones, from the most superficial, with a higher water content and chondrocytes, to a deeper area of calcified cartilage that is over the subchondral bone [16].
Subchondral bone, together with the osteochondral unit, completes the triad of elements with a predominant role in the biological maintenance of the joint. This structure consists of a plate of cortical bone from where the bone marrow and trabecular bone areas emerge. The importance of the subchondral bone lies in its communication with the cartilage, providing this tissue with at least 50% of the oxygen and glucose requirements. This communication not only is limited to the nutritional contribution but also covers the cellular and molecular signaling that participates in the cartilage homeostasis. Besides this, it is also a source of MSCs and participates in absorbing joint loads along with the other elements mentioned above [17].
The joint adaptability is both mechanical and biological, and it is in this last component where the action of regenerative medicine could positively influence. All the structures and tissues described above participate in joint stability by adapting to the different alterations and stimuli received, ultimately maintaining a healthy cartilage. Because of the “mechanical stabilizers” of the joint, the mechanical loads and forces that it receives become molecular and cellular stimuli that are maintained at physiological levels. These stimuli activate the chondrocyte gene expression, allowing them to synthesize proteins, such as proteoglycans, collagen, and metalloproteases, that ensure the integrity and renovation of the articular cartilage [18]. The continuous adaptation of the cells to the mechanical stimuli they receive in order to maintain the adequate extracellular matrix is based on a very delicate anabolic/catabolic balance, and any mechanical or biological alteration can break it resulting in joint degeneration [19].
The balance present in the joint may be broken because of multiple causes (Figure 2). For example, injuries of the tissues involved in the mechanical stabilization of the knee could entail an abnormal load distribution. This would cause an unsatisfactory shock absorption into the joint, and the stimuli generated would exceed the physiological level [20]. Lifestyle can also have an impact on the generation of pathological stimuli. Both uncontrolled physical activity and sedentary lifestyle lead to an excess or defect of stimuli, respectively. The result is a biological and cellular malfunction and, consequently, a defective tissue renewal. In addition, pathologies and biological disorders such as inflammatory processes or those affecting the structures responsible for maintaining and nourishing the cartilage could also cause cellular failures that lead to imbalance and joint degeneration.
Joint degeneration processes. Different causes such as abnormal mechanical loads, injuries of stabilizing structures, or pathologies and biological disorders cause nonphysiological stimuli that modify the gene expression of cells. As a consequence, the extracellular matrix degenerates, activating pro-inflammatory pathways that create a harmful environment and joint degeneration.
The multifactorial nature of this pathology makes it difficult to know the exact origin of the triggered processes as well as their sequence and timing. These events take place with special importance in the interaction between the synovial membrane, cartilage, and subchondral bone. Regardless of the original cause, one of the main consequences of this imbalance is the deterioration of the extracellular matrix and the generation of degradation products that are released to the synovial fluid [21]. The cells of the different joint tissues such as chondrocytes, synovial macrophages, osteoblasts, or fibroblast interact with these molecules, which act as Toll-like-receptors (TLRs) and damage-associated molecular patterns (DAMPs). As a consequence of these interactions, the intracellular pathway of the nuclear factor kappa β (NF-kB) is activated, connecting the mechanobiological program and the inflammatory response. The gene expression of the affected cells shifts to an inflammatory pattern synthesizing molecules, namely, interleukins (IL-1b, IL-6, IL10), prostaglandins (PEG-2) and other pro-inflammatory biomolecules, and cytokines (necrosis factor alpha (TNF-α), interferon gamma, or nerve growth factor (NGF)). Pathological levels of these molecules also interfere in physiological repairing responses. For instance, the action of MSCs from the bone marrow is altered by high levels of transforming growth factor beta (TGF-β), compromising their modulating and repairing functions [22].
All the harmful biological environment generated by this event cascade leads to pathological outcomes in the cartilage, synovium, and subchondral bone. Chondrocytes of cartilage turn into a much more active state, forming cell clusters and increasing their proliferation. They also increase the synthesis of both extracellular matrix proteins and enzymes, causing an altered remodeling of the matrix with hypertrophy and calcifications [19]. Concerning the synovium, inflammation occurs in the early stages together with macrophage infiltrates and an increased synovitis in the advanced stages [23]. Communications between the cartilage and subchondral bone are increased due to the presence of fissures and microcraks, in addition to the remodeling of this tissue with fibroneuroangiogenesis because of the overexpression of molecules like TGF-β and vascular endothelial growth factor (VEGF) [24].
Moreover, the negative effects arising from joint degeneration can affect other tissues as well [8]. For example, studies conducted in the meniscus of patients with arthrosis showed a tissue with increased vascularization and nerve terminals, with the unstructured extracellular matrix, abnormal cell organization, and cell death [25]. Likewise, ligaments with osteoarthritic patients also showed calcifications and disorganized collagen fibers [26]. Finally, muscle tissue is also affected by inflammation produced in joint degeneration, showing fibrosis, collagen depositions, and muscle wasting [27]. Considering all this, it is clear that joint degeneration is not a sole cartilage disease. Instead, it affects all the elements present in the joint, and, therefore, it should be clinically tackled taking into consideration all of them in order to reverse or slow down the degenerative progression.
PRP is an autologous biological therapy framed in the regenerative medicine whose basic principle is to obtain a fraction of blood plasma that contains platelets at a higher concentration than in the blood. From the pharmacological perspective, it is very difficult to define it since the PRP presents a large number and variety of active substances, even often antagonistic. Its therapeutic potential lies both in the biomolecules present in the plasma and in the platelet and its content that is the core element of this therapy.
The platelets are produced by the megakaryocytes of the bone marrow, which migrate to the endothelial barrier after maturation and project their prolongations releasing into the bloodstream the proplatelets or precursors that will generate the platelets [28]. Platelets are discoid and anucleated blood elements with a diameter of 2–3 μm; their blood concentration is 150.000–400.000 platelets/μL with a life span of 7 to 10 days. Platelets are limited by an external plasma membrane that contains a large network of receptors that trigger intracellular signals that allow platelets to perform their numerous functions. Among them glycoprotein Ib (GPiB) and glycoprotein VI (GPVI) receptors can be found, which are involved in functions related to homeostasis, the main function of platelets. GPIb and GPVI bind to von Willebrand factor (VWF) and collagen when there is a discontinuity in the endothelial barrier that exposes the extracellular matrix. These interactions cause conformational changes in platelets and allow them to bind to fibrinogen, tissues, and other platelets to form the thrombus that will participate in tissue repair. In addition, this platelet activation also causes the release of their internal content that has regenerative abilities and justifies the use of PRP.
The internal content of platelets is stored in different granules called dense granules, α-granules, and lysosomes. The material present in these granules may have been synthesized by the original megakaryocyte as well as captured by platelets by endocytosis. The α-granules are those that have a higher content of active biomolecules related to tissue repair. Hundreds of these molecules have been identified, including adhesive proteins, fibrinolytic and coagulation factors, antimicrobial molecules, cytokines, and growth factors, among others. These last two groups of molecules participate in tissue repair and regeneration processes such as angiogenesis, chemotaxis, migration, or cell proliferation [29]. When platelets are activated, not only these molecules are released but also other elements such as platelet microparticles, which are involved in anti-inflammatory processes, or exosomes. Exosomes are small vesicles of 100–400 nm that carry several proteins in addition to other biomolecules as genetic material. Although not much is known about these platelet exosomes, it has been found that they are very important in cellular communication [30].
The activation of the PRP platelets causes the release of platelet content related to tissue repair to the outside, and it joins to the circulating biomolecules in the plasma. Thus, the levels of many growth factors will depend on the platelet concentration of the PRP. Among these platelet growth factors, there is platelet-derived growth factor (PDGF), which is a potent chemotactic for several cell types and has an important effect on tissue repair over tissues such as cartilage and meniscus. Another growth factor with a large presence in platelets is TGF-β, whose effects are varied and can be of different nature depending on the molecules and cells with which it interacts. It influences early responses in tissue repair, on the differentiation processes of mesenchymal stem cells, and on the maintenance of cartilage and subchondral bone. Other regulatory factors in tissue repair are VEGF, epidermal growth factor (EGF), or basic fibroblast growth factor (bFGF) with key roles in cell migration, proliferation, differentiation, or angiogenesis. In addition, circulating molecules such as insulin-like growth factor type I (IGF-I) or hepatocyte growth factor (HGF) have also crucial importance in the effect of PRP; they are growth factor enhancers of regeneration processes as well as modulators of inflammatory processes [31].
Therefore, PRP is a cocktail of thousands of biomolecules from plasma and platelets that regulate hemostasis, coagulation, tissue repair and regeneration, inflammation, cellular behavior, or defense against microorganisms, among other biological processes. All this therapeutic potential depends largely on its composition, which may vary according to the method used to obtain it. As a result, there is a wide variety of PRP products as will be explained below.
As stated previously, the PRP obtaining technique is used to achieve a fraction of blood plasma with higher levels of platelets than blood. The first step consists in the collection of a small volume of peripheral blood from the patient using tubes with anticoagulant—to prevent blood clotting. Different types of anticoagulants can be used such as sodium citrate and ethylenediaminetetraacetic acid (EDTA), which chelate calcium and prevent the coagulation cascade, or heparin that inhibits thrombin. However, sodium citrate is the most recommended anticoagulant since it ensures a better preservation of platelets [32]. It also causes less secretion of microvesicles that are the result of platelet activation, which is increased when EDTA and heparin are used as blood anticoagulants [33].
After blood collection, a centrifugation process is performed, whose force and time vary according to the methodology and, hence, the PRP formulation to be obtained. Centrifugation has to generate sufficient force to create a gradient that separates the blood into different fractions but without damaging its components (Figure 3). These centrifugations can be single or double, with a centrifugal force of between 350 and 2000 g and a centrifugation time of 3 to 15 minutes depending on the method used. Thus, the blood is divided into a lower fraction of red blood cells, a thin layer of leukocytes or buffy coat, and finally the plasma fraction with platelets, which gradually decrease their number in the uppermost areas. This last layer will constitute the PRP, and depending on the centrifugation process, the number of platelets may vary. However, a higher number of platelets are not strictly linked to an improved effect of PRP. In fact, several studies have reported that an excessive concentration of platelets may have inhibitory effects on cell proliferation or differentiation in populations such as tenocytes or adipose tissue-derived stem cells. Thus, the optimal platelet concentration for an optimized function is considered two- to threefold compared to blood levels [34, 35].
Obtaining Platelet-Rich Plasma. After blood fractionation, the platelet-enriched plasma fraction is obtained. The activation of this fraction causes the release of the platelet content that together with the plasma molecules constitutes the effector biomolecules of the PRP. It also generates the polymerization of the fibrinogen that will create a network of fibrin where these biomolecules will be trapped, and that will be released progressively.
When separating the PRP from the rest of the blood fractions, there is the option to include or not the leukocyte layer, thus obtaining different PRP products, which will be detailed below. Although in some musculoskeletal disorders the use of Leukocyte-Rich PRP (LR-PRP) need further research, there is an increasingly broad consensus by which the use of leukocyte-poor PRP (LP-PRP) preparations is recommended for joint degeneration [36]. The inclusion of leukocytes in the PRP generated pro-inflammatory molecules that had negative effects on cell proliferation and chondrogenic differentiation as well as a worse regeneration of articular cartilage [37]. However, the fraction of red blood cells must be discarded in order to avoid the presence of erythrocytes in the PRP. The presence of erythrocytes in the PRP entails their own degradation processes such as hemolysis and eryptosis. As a result, products that promote inflammation and cellular stress are generated, which would hinder the beneficial action of PRP [38].
The last step in the process to obtain PRP is the activation of platelets, through which its platelet content not only is released but also triggers the polymerization of fibrinogen in a fibrin mesh that traps the molecules. Thus, a controlled release system that delivers the molecules as it degrades is obtained. Activation can be exogenous either by physical methods such as freeze–thaw cycles or by the addition of certain substances (calcium chloride, thrombin). Some methods propose endogenous activation in which PRP is administered without prior activation and platelets are physiologically activated inside the body [39]. However, the use of exogenous activation allows a more versatile PRP, and depending on the time that has elapsed since the activation, different formulations are achieved at the point of care. The addition of calcium chloride as an activation method avoids the use of exogenous biological elements such as thrombin. It also prevents local hypocalcemia that can be caused by the calcium-chelating anticoagulants previously used in blood collection to prepare the PRP. Thus, PRP can be used as an injectable liquid formulation immediately after activation or as a fibrin membrane-clot minutes after adding the activator. In this case, and due to its consistency, this formulation can be used as a biological and autologous scaffold in surgical interventions that promote tissue repair [40].
As mentioned above, many variables may be involved in the obtaining process. It is not the intention of this chapter to delve into the large number of PRP types that exist both in the market and in the scientific literature. However, it is important to mention the variables that condition not only the type of PRP and therefore the different biological effects but also the classification systems (Table 1).
Variable type | Dohan [41] | Mishra [42] | PAW [43] | PLRA [44] | DEPA [45] | MARSPILL [46] |
---|---|---|---|---|---|---|
Composition | Leukocytes Fibrin | Platelets Leukocytes | Platelets Leukocytes Neutrophils | Platelets Leukocytes Neutrophils Erythrocytes | Platelets Leukocytes Erythrocytes | Platelets Leukocytes Erythrocytes |
Activation | — | Activation | Activation | Activation | — | Activation Light |
Others | Efficiency | Method Image guided Spin | ||||
— | — | — | — | |||
Variables analyzed in the different classification systems.
The three main variables that condition the obtaining of PRP, namely, number of platelets, presence or not of leukocytes, and activation, generate many different products under the PRP term which are necessary to differentiate. Not only a wide variety of products have emerged but also several classification systems that have attempted to clarify the inconsistency that accompanies the term PRP. Initially, the main difference was the presence or not of leukocytes. In the first classification of Dohan et al., PRPs could be distinguished in leukocyte-poor PRP and Leukocyte-Rich PRP, besides contemplating the fibrin presence [41]. Subsequently, Mishra [42] and DeLong [43] took into consideration the number of platelets and the activation of PRP. In the following classifications, the presence of erythrocytes [44] was also mentioned, and in recent years aspects such as recovery efficiency or centrifugation and application methods were addressed [45, 46], trying to classify as much as possible the different PRP products (Table 1).
As if that were not enough, new denominations are being coined in products derived from blood but that share the fundamental principles of PRP. This is the case of the Platelet-Rich Fibrin. These types appeared initially in the Dohan classification and refer to the fibrin clots that are formed either by centrifuging the blood without anticoagulants or by activating the liquid PRP and waiting for the formation of fibrin net, as mentioned above. A product derived from this is the hyperacute serum that is obtained with a procedure similar to that of the PRP but without using anticoagulants. Thus, after centrifugation of the blood, the upper fraction is a fibrin clot (Platelet-Rich Fibrin), which is squeezed to obtain the hyperacute serum [47]. It contains all the plasma and platelet biomolecules without coagulation proteins such as fibrinogen, namely, the product obtained is almost identical to the exudate gradually released from the fibrin net achieved after the activation of PRP. However, many growth factors present in the hyperacute serum will be eliminated quickly after its injection into the affected area due to its short half-life, whereas if they are released in a controlled manner as in the activated PRP, its time of action will be longer [48].
The lack of standardization is one of the main limitations in the application of PRP. Although all these products are called PRP, their composition may differ from many others and as a consequence their biological effects and clinical results. For instance, the presence of leukocytes determines the levels of pro-inflammatory molecules, and the activation or not of platelets affects the biomolecule release kinetics. Therefore, the comparison of PRP studies, assuming that it is the same product, yields contradictory data, so it is necessary to specify the type of PRP used in these works [49].
As PRP is a product that contains a large number of bioactive molecules, it is wrong and impossible to define the effect of the PRP based on the isolated actions of each molecule. The biological effect of PRP depends not only on its molecules but also on its synergistic effect, which also considers interactions between molecules. Indeed, many PRP molecules are activated in the presence of others, or on the contrary many have antagonistic effects, conditioning the final effect of PRP.
Multiple actions are attributed to the PRP in the treatment of pathologies of the musculoskeletal system. However, this chapter will be limited to highlighting the effects that have the greatest impact on improving joint degeneration (Figure 4).
Biological effects of Platelet-Rich Plasma on joint degeneration. The inhibition of the intracellular signaling pathway NF-Kβ, the reduction of reactive oxygen species, and the promotion of M2 macrophages cause the drop of pro-inflammatory molecule levels, achieving an anti-inflammatory effect. In addition, this decrease in pro-inflammatory molecules such as prostaglandin E2 achieves an analgesic effect, which is also favored by the activation of endocannabinoid systems. On the other hand, PRP modulates the cellular response, stimulating the proliferation of chondrocytes and synoviocytes, which increase the production of the substances responsible for lubrication. This modulation also affects mesenchymal stem cells, which increase their chondrogenic potential and decrease their aberrant and senescent forms.
Due to the complex OA pathophysiology, inflammation can be both the cause and consequence of other pathological processes. Because of this, it is important to reverse the pro-inflammatory environment of this pathology and restore homeostasis of the joint to promote tissue repair. Many of the PRP molecules participate in the regulation of these inflammatory processes, which are key in the progression of the pathology. The anti-inflammatory effect of PRP is achieved through the action of its biomolecules at different levels. Molecules such as IGF-1 or HGF restore the original acquiescent state of cell populations from an inflammatory state because of joint degeneration. This effect occurs through the inhibition of the intracellular signaling pathway NF-Kβ by these molecules, and, as a result, the generation of pro-inflammatory molecules such as IL-β or TNF-α is reduced [50, 51]. The use of PRP rich in leukocytes can be especially important in this mechanism of action since, instead of inhibiting this inflammatory pathway, they activate it due to the presence of certain pro-inflammatory molecules in this type of PRP [37]. This inhibitory effect not only is limited to chondrocytes but also affects other cell populations such as fibroblast, osteoblasts [52], or macrophages [53]. The consequence of silencing this pathway in the different cell types of the joint is the drop in the inflammatory molecular levels of the synovial fluid, relieving the inflammatory environment [54].
Within its anti-inflammatory action, PRP also acts on macrophages by changing its phenotype. This effect may be indirect due to the decrease in pro-inflammatory molecules or direct by a direct action on the PRP components such as the microparticles produced by platelet apoptosis. The result is a phenotype shift of the macrophages from inflammatory (M1) to reparative (M2) phenotype, where the reduction of inflammation is favored and tissue repair is stimulated [55]. This effect is especially important in macrophages present in the synovial membrane. The increase in anti-inflammatory macrophages to the detriment of pro-inflammatories results in a decrease in inflammation of the synovial membrane, which is a hallmark of OA [56]. This polarization towards a reparative state may be due to the action of the interleukin 1 receptor antagonist, present in the PRP, which in addition to avoiding the inflammatory effect of IL-1 promotes the repair phenotype M2 of macrophages [57].
The inflammatory environment in the osteoarthritic joint is also potentiated by the increased presence of reactive oxygen species (ROS), which participate in the OA pathogenesis through synovium inflammation, cartilage degradation, or subchondral bone dysfunction [58]. PRP activates the antioxidant response element through the intracellular signaling pathway NrF2-ARE in osteoblasts [59]. This achieves an antioxidant and protective effect in these cell populations, avoiding damage caused by ROS increment.
The interaction of PRP biomolecules in the mechanisms that trigger inflammation results not only in a decrease in the levels of pro-inflammatory molecules and ROS but also in a promotion of gene expression related to anti-inflammatory action. It has recently been shown that gene expression of enzymes related to aggrecan destruction and metalloproteinase modulation, namely, metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) and tissue inhibitor of metalloproteinases-1 (TIMP-1), are decreased in cartilage and synovium under the presence of PRP. However, gene expression related to the formation of collagen 1 and aggrecan is increased [60].
Pain is one of the most characteristic symptoms of OA and one of the most limiting factors for the patient, affecting its functionality and quality of life. One of the main causes of pain associated with joint degeneration is the inflammation that occurs. Solving the inflammatory problem would partly relieve the pain of the OA patient. This relief is one of the most observed effects in clinical studies since it is the most studied variable. However, it is necessary to deepen the mechanisms of action by which the PRP achieves the analgesic effect. During the inflammatory processes, molecules are generated by resident macrophages outstanding prostaglandin E2 (PGE2), which is one of the main causes of the inflammatory pain [61]. As mentioned earlier, PRP favors the change in macrophages from pro-inflammatory to anti-inflammatory phenotype as a consequence of the production of PGE2 and other pro-inflammatory molecule reductions [56]. In addition, the action of the PRP over the NF-Kβ pathway could also reduce the levels of substances that stimulate the nociceptors of the joint synovitis [62]. Therefore, inhibition of the synthesis of these substances is one of the mechanisms of action by which PRP reduces pain.
Although the action on inflammation may be the most predominant mechanism in pain relief, the implication of other pathways has been studied, namely, the peripheral endocannabinoid-mediated mechanism, which could be a promising therapeutic target in the synovial tissue of OA patients [63]. The influence of PRP on this signaling system is associated with the stimulation that occurs in the cells located in inflammatory environments. In the presence of PRR, these cells would generate analgesic substances such as anandamide and 2-arachidonoylglycerol, which are agonists of cannabinoid receptors 1 and 2. This effect is observed both in vitro and in vivo, with a lower nociceptive response in treated animals [62].
One of the problems associated with osteoarthritis is the lack of lubrication and therefore the increased friction in the joint. In a healthy joint, the synovial fluid has a natural lubricant function due to the presence of hyaluronic acid. The alteration of the components of the synovial fluid worsens the lubrication, deteriorating the cartilage. In addition, this layer of lubricant decreases progressively as the disease worsens, creating a vicious circle [64]. Restoring joint lubrication is one of the priorities to improve the course of the disease, and it is the purpose of intra-articular hyaluronic acid infiltrations [65].
The application of PRP also may restore joint lubrication through several mechanisms. First, it has a stimulating effect on the chondrocytes and synoviocytes, due to the fact that it not only enhances its proliferation but also increases the production of hyaluronic acid, improving the lubricating capacity of the synovial fluid [66, 67, 68]. Secondly, PRP also influences lubrication through the superficial zone protein (SZP) or lubricin. This protein synthesized by chondrocytes and synoviocytes acts as a chondroprotective barrier against direct contact in joints. PRP improves lubrication both directly, since it contains endogenous SZP, and indirectly by stimulating the SZP secretion by articular cartilage and synovium [69].
All the effects described above are generated through the interaction between growth factors and cell membrane receptors, triggering intracellular pathways and affecting gene expression that generates the biological effects. In addition to these, which are the most influential in the asymptomatic relief of OA, namely, inflammation, pain, and lubrication, there are other trophic and regulating effects that, although they do not have such a drastic clinical outcome, are necessary to promote tissue repair and reverse or slow down the disease.
PRP has demonstrated its biological effect over the chondrocytes of articular cartilage and its consequent impact on cartilage repair. Fice et al. published a systematic review including numerous in vitro and in vivo studies that showed the action of PRP on the cellular response [70]. On the one hand, it acts on cellular behavior, increasing growth, migration, and proliferation rates and reducing negative effects such as apoptosis. On the other hand, PRP enhances the synthesis of glycosaminoglycans (GAGs), proteoglycans, and collagen, improving the production of extracellular matrix.
In addition, stimulation of cartilage repair is also conditioned by the action of MSCs. They are able not only to differentiate into cells with specialized functions such as chondrocytes, osteoblasts, and adipocytes but also to release molecules and cellular signals that regulate the repair processes [71]. The behavior of MSCs in OA is modified, increasing in number in synovial fluid as the severity of the disease increases [72]. These MSCs come from resident joint niches such as the synovial membrane, the surface of the articular cartilage, and the subchondral bone, once again confirming the involvement of all the joint structures in the development of OA [17]. In this pathological environment, these cells have their function altered, losing their restorative activity [73]. Bearing this in mind, mesenchymal stem cells are considered a therapeutic target for the PRP to modulate its behavior and restore its physiological functions. Muiños-López et al. observed a decrease in MSCs in synovial fluid of patients with severe OA after the application of PRP directly into the subchondral bone [74]. The regulatory capacity of PRP on MSCs may be due to the direct action on their cellular response as well as the improvement of the biological environment in which the cells reside. Bone marrow-derived MSCs treated with PRP showed an increase in proliferation and chondrogenic capacity [75]. This increased proliferation was also observed in human adipose-derived stem cells, although their chondrogenic differentiation potential was retained [76]. Restoring tissue homeostasis where MSCs reside, for instance, by decreasing inflammation by inhibiting pro-inflammatory molecules, also improves the action of these cells. The attenuation of a TGF-β-mediated signaling excess in the subchondral bone during OA restores the dysfunction of the MSCs, preventing cartilage degeneration [77]. Liu et al. observed that intraosseous infiltrations of PRP promoted MSC cell proliferation and osteogenesis in an in vivo study, whereas adipogenesis, senescence, and oxidative stress were decreased [78].
The transfer of the PRP from the laboratory to the clinical application has been very fast with extensive worldwide expansion. This has occurred in part because of its ease of obtaining and its high safety as an autologous product, and, as a consequence, more and more clinical studies are being published on the use of PRP in OA. It is not the intention of this chapter to analyze all these studies but to highlight the most relevant aspects of this translation. The latest published meta-analyses concluded that the use of intra-articular PRP infiltrations achieves effects on symptoms such as pain relief or improved function better than the use of hyaluronic acid or placebo especially for the long term [79, 80, 81]. Based on these data, it could be accepted that the PRP has evolved from being a promising alternative to a real option for clinicians and patients.
However, it should not be forgotten that it is necessary to continue to carry out high-quality clinical studies to clarify possible doubts and achieve the ideal protocol for both obtaining and applying PRP products [82]. Some of the clinical studies carried out have attempted to elucidate this type of questions, the presence of leukocytes being one of the most critical issues. Several authors have studied the clinical effect of including leukocytes in the PRP. Mariani et al. studied the pro-inflammatory effect that intra-articular infiltrations of Leukocyte-Rich PRP could have. Surprisingly, and contrary to the in vitro studies, patients who received this treatment did not experience an increase of pro-inflammatory molecules in the synovial fluid or plasma in the short or long term [83]. These data were confirmed in a meta-analysis where there were no differences in adverse reactions between PRP with and without leukocytes, being very rare and local such as pain and inflammation. However, as far as efficacy is concerned, this same work carried out by Riboh et al. showed that PRP poor in leukocytes had significantly better results than those obtained by hyaluronic acid and placebo, whereas this difference did not occur in PRP rich in leukocytes. Therefore, according to the studies carried out in this matter, the inclusion of leukocytes in the PRP does not affect the safety of the product but does diminish its effectiveness in the treatment of knee OA [36]. In spite of these advances, it is necessary to continue studying the rest of the composition variables that may condition the clinical response of the PRP, such as platelet concentration. Recent studies suggest that a concentration below fivefold blood platelet concentration is recommended [84].
Not only the variables related to the obtaining or composition of the PRP products condition the clinical effect of this therapy but also the different methods of application. Several clinical studies addressed the effect of a single or repeated administration of intra-articular infiltrations of PRP. A first group of studies focused on analyzing the differences between a single infiltration of PRP and several repeated infiltrations every 1 or 2 weeks. These studies demonstrated that PRP obtained better results than control treatment and, in addition, patients who received repeated intra-articular infiltrations of PRP achieved better clinical response on items such as pain, symptomatology, and function [85, 86, 87]. Other studies analyzed the effect of applying several cycles of PRP infiltrations, referring to a cycle as a series of repeated infiltrations in a short period of time. Gobbi et al. compared the efficacy of administration of one PRP cycle against two PRP cycles separated by 1 year, one cycle being three intra-articular infiltrations of PRP in 1 month. In both groups, there was an improvement in patients 1 year after the first cycle, which was accentuated at 18 months after the application of a second cycle [88]. Vaquerizo et al. conducted a similar study comparing patients treated with one PRP cycle with patients treated with two PRP cycles separated by 6 months, one cycle being three weekly intra-articular PRP infiltrations. The results showed that although there were no significant differences in pain improvement, patients who received two cycles had better symptoms and functionality 1 year after treatment [89]. Thus, the different studies that analyze this variable recommend the application of repeated PRP injections instead of isolated ones.
Following with the PRP administration modality, it is important to remember that the mechanism of action of PRP biomolecules is cell stimulation and improvement of the biological environment to favor tissue repair. Furthermore, as explained at the beginning of this chapter, OA is an alteration of the whole joint and not just a few elements. Considering these two assumptions, it would be advisable to act on the majority of the tissues involved in the joint and especially on those that perform a more predominant biological function. When PRP is intra-articularly administered, it soaked the articular space, reaching and acting on the cells present both in the synovial membrane and on the articular surface. However, this route of administration does not reach the subchondral bone which communicates with the cartilage, especially in OA case, and it is fundamental both in the maintenance of homeostasis and in the pathophysiology of joint degeneration [17]. In order to extend the range of action of the PRP and also act on the subchondral bone, Sánchez et al. described the technique of PRP intraosseous infiltrations (Figure 5). This method of application combines conventional intra-articular injection of PRP with intraosseous infiltrations into the subchondral bone of the femoral condyle and tibial plateau in severe cases of knee OA [90]. Afterward, this technique was adapted to treat advanced cases of hip OA, combining intra-articular infiltration with intraosseous infiltrations into the femoral head and acetabulum [91]. In both cases, intraosseous administration must be assisted by imaging, ultrasound, or fluoroscopy, to ensure correct delivery in the required area.
Intraosseous administration of PRP. Intraosseous PRP administrations allow the subchondral bone to be reached and its therapeutic effect to be extended. Intraosseous infiltrations are applied in the femoral condyle (A) and tibial plateau (B) in patients with knee OA and in the acetabulum (C) and femoral head (D) in cases of hip OA.
The first published works carried out using this technique provided promising results. In a pilot study performed with patients who presented knee OA of grades 3 and 4 according to the Ahlbäck scale, pain was significantly reduced, and an increase in joint function was observed at 6 months after receiving the combination of intra-articular and intraosseous PRP injections. In addition, the number of MSCs present in the synovial fluid decreased after this treatment [92]. This finding was not observed in patients treated only with intra-articular infiltrations, suggesting the importance of the subchondral bone in the modulation of cellular response in joint degeneration [74]. Following the same trend, an observational study compared the intra-articular administration of PRP versus the combination of intra-articular and intraosseous injections in patients with severe knee OA. The results of this study showed that although there was no difference between both groups at 2 months after treatment, patients who received the PRP intraosseously showed clinically superior results at 6 and 12 months [93]. Su et al. conducted a clinical trial in which, in addition to comparing intra-articular against intraosseous injections, they used hyaluronic acid as a control treatment. The patients enrolled in this study presented knee OA of grades 2 and 3 according to the Kellgren-Lawrence scale. The results achieved with treatment based on intraosseous infiltrations of PRP were superior to those obtained with both intra-articular PRP and hyaluronic acid [94]. No severe adverse effects were reported in any of these studies, and they were limited to pain after infiltrations. One of the characteristics of the subchondral bone in patients with knee OA is the presence of fibroneurovascular proliferation. Although the PRP contains proangiogenic and profibrotic molecules, no basic or clinical study showed the uncontrolled induction of this effect after the application of intraosseous PRP [22].
Finally, intra-articular injections of MSCs derived from various sources associated with PRP were analyzed in some studies. The vehiculization of MSCs in PRP could entail an improvement in cell viability and may be translated into better clinical results. Although studies performed with both bone marrow [95, 96]- and stroma fraction [97, 98]-derived MSCs showed improvement in these patients after the application of this therapeutic combination, the association of PRP with the MSCs did not lead to a greater clinical improvement in patients. However, the therapeutic potential of the synergy of both therapies justifies further research in this field.
Joint degeneration is a pathology that affects a large part of the population, deteriorating their quality of life being disabling in many cases. It is also related to aging and unhealthy lifestyle habits; thus it is expected that its prevalence will increase in the coming years, assuming a great cost to health systems. Current conventional treatments focus on symptomatic relief without addressing the cause of the disease. Because of this, new treatments based on regenerative medicine are emerging in order to expand the therapeutic arsenal and delay or prevent joint replacement, which is currently the only definitive solution for patients. Moreover, in order to achieve an optimal treatment for joint degeneration, it must be understood that the joint works as a whole organ. All elements of the joint participate in the maintenance of homeostasis, the synovial membrane, cartilage, and subchondral bone being key for biological balance.
This balance could be maintained or restored by means of several biological therapies such as PRP that is a cocktail of plasma and platelet biomolecules, and it is obtained after fractionating small blood volumes by centrifugation. PRP has a great versatility since it allows its use through different types of formulations, being able to be applied both in outpatient infiltrations and surgical interventions. The therapeutic potential of PRP in joint degeneration lies in its ability to modulate inflammation, lubrication, and pain, acting on different cell populations to create a biological environment conducive to tissue repair. However, the variety in the composition of PRP products leads to different biological effects and consequently contradictory clinical results. It is, therefore, necessary to identify and characterize the PRP used in order to advance both research and clinical practice.
The success of the PRP also depends on the method of clinical application. The administration of PRP has to cover the main joint tissues so that the biological effects of PRP act over the cells of in order to reverse the course of the pathology. Although the safety and ease of obtaining PRP have allowed a quick transfer from the laboratory to the hospital, much is still unknown about this therapy, and further basic and clinical research is needed.
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