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278 V. Dini et al.
Fig. 3 Ultra-high frequency ultrasound clip acquired at the edge of a venous ulcer with Doppler detection of blood ow
Finally, by means of UHFUS Doppler it is possible to study the microcirculation within the wound edge and bed with the possibility of providing new parameters for the evaluation of wound healing.
Nowadays many manufacturers are developing probes with windows for the study of skin and soft tissues capable of connecting to smartphones and tablets (both wired and wireless).
These devices enable the reduction of costs, but also make the use of ultrasound applicable in every dermatological ambulatory.
They are also versatile. They transmit live images to higher level centres or teleconsultations for medical and nursing ambulatory.
In conclusion, it is now clear how the use of US in wound imaging can be an added value not only in diagnosis but also in therapeutic management, but other studies are needed to nd new ultrasound parameters performed with the latest generation technologies.
New ultrasound instruments are also equipped with software that through the same probe can also allow elastography to be obtained.
Elastography is a dynamic technique that uses ultrasound to noninvasively assess the mechanical stiffness of tis sues by measuring their distortion in response to external stretching.
A transducer is applied to the skin and mechanically stressed on the tissues by compression and decompression of the skin; this stress, measured as axial dis­placement of the tissue, is visualized as an elastogram.
By convention, the elastogram is color-coded, and tissues with high deforma­bility are shown in red. the greater the stiffness, the more intense the blue color.
Wound Measurement is an Essential Part of Wound Management 279
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This data can be semiquantitative using a color-based visual scoring system or in the form of strain ratio measurements usually provided in elastography software (Gennisson et al. 2013).
Discussion
Currently there is state-of-the-art imaging methods for wound care, and from the time of their rst use they have been of paramount importance in wound man­agement. The versatility of the new, increasingly portable, increasingly powerful instruments that can explore every morphological and functional parameter from microvascularization of the smallest cutaneous vascular plexuses, calculating the velocity of a single red blood cell within a capillary, to viewing the single cell of neoepithelium. Imaging methods can also measure and thereby provide a concrete and valuable aid to clinicians in increasing diagnostic and therapeutic, and therefore prognostic performance.
We live in the world of articial intelligence where quantifyingand providing algorithms is critical. Nowadays, few of these presented methods have relevant data such as to affect wound outcomes in a certain way. Large-scale use and stan­dardization of each method is mandated to make advances in wound imaging.
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Translation of Wound Devices into PracticeA Myth? Translation is the Process of Taking an Invention Through to Clinical PracticeHow Successful Are We?
Mark Richardson and Raj Mani
Abstract
In these times as we emerge from the pandemic caused by COVID-19, Translation should be embraced as the procedure which envelopes the journey of a concept into practice so as to maximise the benets of research and development. In wound care, Translation should stand for the evolution of a protocol, innovative device or drug through safety and clinical efcacy testing into everyday clinical use. This is an enormous challenge, so is the challenge of dening standardised care for chronic wounds and conveying it into routine use. The process is arduous, it also requires huge resources but it needs to be done. An outstanding example of successful translation is the currently used Combined Artemisinin treatment for malaria. The steps involved in translation as applicable to chronic wound management are discussed with a few highlighted cases in this chapter.
Keywords
Chronic Wound ManagementTranslationInnovation
The term translation in relation to medical products and Chronic Wound Man­agement is normally viewed as the turning of new clinical and applied research into products (drugs or devices), therapies, or protocols that can be usefully applied to the maximum benet of patients (Tolikas et al. 2017). In the context of this book the denition should also be broadened to include the ways and means of
M. Richardson (&) York, England e-mail: markcrichardson35@gmail.com; mcr1d17@soton.ac.uk
R. Mani Shanghai Jiao Tong University School of Medicine, Shanghai, China
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. Mani (ed.), Chronic Wound Management,
https://doi.org/10.1007/978-3-031-26110-7_14
285
286 M. Richardson and R. Mani
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discovering newperhaps even more useful and impactfulapplications for technology or practice that may already exist and have been adopted in some way. Therefore a more comprehensive denition for Translation would be that of pro­gressing the process of clinical innovation through to all of the most benecial applications in clinical practice for patients.
The question can then be asked should the Medical industry lead or follow the
clinician in this translational process? This tension is best thought of as a synergistic partnership between industry and the academic/clinical community. In order to solve unmet patient needs then there are these two powerful pipelines of translation: one is clinical and a nother is technological that can be focussed on satisfying and meeting a clinical need.
Clinicians are clearly the parties who are most fully aware of unmet needs in their
patient groups. This can be in terms of therapies, treatments or interventions needed to address the problems or deciencies they face in patient care. In some cases they will themselves be looking for already established innovations and practices and considering if these could be adapted or trans latedto the needs of their own patients. Some of them will be innovating and exploring on a regular basis (Maj­mudar et al. 2015) in the techniques and practices they apply in order to solve clinical problems and needs they face. Through this approach they may themselves become the pioneers and innovators of new therapies. Industries in the medical sector also have a place in this process and are themselves continually seeki ng to understand such unmet needs in areas that t their business strategy, so that they can direct their own innovation engines and processes to developing novel interventions. They would then seek to translate these into clinical practice and commercialisation in partnership with healthcare professionals. Indeed, a clinician may well approach a company to seek their help if they see no immediate solution to hand or if they need or require wider resources, to move an idea forward collaboratively. This partnership can provide the perfect team to translate a clinical solution to everyones, and most importantly, the patients, benet (Tolikas et al. 2017).
Gaining Approval for Clinical Use of an Innovation
The process of translation requires several steps to be completed once a concept, idea or invention has been realised either as a device, drug, or protocol. Usually a regulatory dossier, a document submitted to a national or regional agency to gain approval for use and product claims, would need to be submitted to a regulatory agency to gain approval for its clinical use whether the product is completely novel or even if this is a new indication or claim for an existing product. Successfully answering and validating key questions from a regulatory authority in relation to the Quality, Safety and Efcacy of the innovation is required in order that the dossier and product can be approved (Gudeppu et al. 2020). These will be further expanded below. In the case of a completely novel product or intervention then all these stages would need to be thoroughly completed and evidence provided. However in
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the case of the translation of an existing product or practice to a new application or indication, perhaps in combination with other therapies as a protocol, then some of these steps could be avoided in discussion with the agency: an example of such a step could be that the quality and safety of the product may already be established. The nal clinical efcacy stage would always need to be established to both support product claims and gain widespread user condence and adoption.
Quality approval in a regulatory dossier would mean establishing that
i. the product is made reliably and reproducibly, and there are adequate checks
and tests in place to assure this on a batch to batch basis
ii. a regulator would also want to know whether a product has a dened and
proven shelf life over which its properties remain within the agreed set boundaries and limits (e.g. drug concentration, pack integrity) such that it can be condently and safely deployed by a clinician or patient.
Safety approval is a key requirement of a clinical intervention of any nature.
This requires the manufacturer or clinician to adequately demonstrate that the patients, for whom the therapy is intended to be used, will come to no harm either acutely or chronically when it is used as prescribed or dened. Depending on the nature of the product or therapy, adequately proving its safety can be costly, lengthy and complex for developers in order to provide data and evidence to satisfy reg­ulators. The regulatory agencys prime role is to protect the public, and to give condence to users in the safety and efficacy of approved products.
Demonstrating efcacy is the ultimate test of verifying to the regulators and
others, if and under what circumstances or conditions, the intervention can be shown to be clinically effective in delivering its intended outcomes. This evidence would support the claims being made on either the product label, instructions for use, advertising and promotion or the protocol. All of these would have to be approved by the appropriate regulators. The evidence provided can be a combi­nation of laboratory, pre-clinical, and clinical data. The clinical data itself, subject to the desig n of the studies, is the highest tier of efcacy evidence and to many clinicians this is the only evidence that will provide them the adequate condence of whether the intervention is efcacious and thereby useful to their patient or user group. Not only is this clinical evidence used in regulatory or other agency sub­missions, which are condential documents, but it will usually be submitted for publication in peer reviewed journals for scientic scrutiny and wider dissemination and access.
Clinical studies are usually considered in terms of 4 main phases each resulting
in more human exposure and evidence development. All of these must have a detailed protocol. These phases have been primarily built around the development of a novel drug but can be also employed to consider how to progress establishment of the efcacy of a device or other intervention for example, a biological product.
Phase I relates to the so-called First in manexposure to a product and can be
considered as a safety study often performed in a small number of healthy vol­unteers who may undergo extensive and intensive monitoring. Phase II focuses on
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establishing an optimum dosage or treatment pattern in the dened patient popu­lation with a number of groups or study arms each receiving different dosages or treatment frequencies. Phase III is a larger study of often `00 s of patients per arm in which the optimum dosage/usage pattern established in Phase II is subjected to a controlled study against either a placebo treatment or current best practice in order to establish efcacy and become aware of any adverse reactions. The gold standard for a Phase III study would be the Double Blind Randomised Placebo Controlled study (DBRCT). In such a study neither the patient or health care professional know which treatment is being applied to the patient. Whilst with topical or oral drugs and/or physical devices it is easy to see how a placebo or a shamdevice could be used, this design of study is not always possible as it may not be possible to be made blindto either the clinician or patient though these would still be classed as RCTs. Post marketing surveillance or Phase IV is the nal phase and this is where efcacy and evaluation continues in the real clinical setting after the product is launched and in widespread use also called Post Market Surveillance.
In addition to the necessary dened studies required to gain a regulatory
approval and satisfy approval of a product claim it is also the case that the collective experience of developments in this sector tells us that the ultimate clinical potential of a device or protocol for example to heal more wounds or to heal wounds more quickly, may best be explored initially by a series of well-designed studies equivalent to the Phase 2 described above in conjunction with Case studies which are uncontrolled observations. These can then be followed by the required con­trolled RCT or DBRCT studies to improve the quality of the evidence and with additional hypothesis driven studies to support the gaining of product claims and additional regulatory approvals if needed. The cost of these large studies and the time and complexity required to execute them demands that they can only usually be performed if funded by Companies or National Agencies for example National Institute for Health Research in the UK.
Without doubt the potential of an intervention to heal is best discovered by a
series of well-designed studies as described above. Larger size studies may be needed in order to adequately and rigorously test hypotheses established in smaller studies and these would need a longer study duration and multiple centres to be enrolled. A real world problem is that higher the sample size, then the higher the trial costs and this may deter the progress of these studies by companies or funding bodies. Furthermore, in order to dene patient groups then inclusion/exclusion criteria may be tightened hence reducing recruitment rates and lengthening studies and further adding to trial costs.
Most countries or economic regions for example EU have a Government reg-
ulatory agency who take responsibility for ensuring that medicines, medical devices and other regulated medical products meet applicable standards of safety, quality and efcacy as described above for example UK/MHRA, US/FDA, China/NMPA, Europe/EMA, Japan/PMDA and CDSCO/India. Approvals for one region may well carry weight or be recognised in another and data can often be adapted across