Machine learning methods for histopathological image analysis

Abundant accumulation of digital histopathological images has led to the increased demand for their analysis, such as computer-aided diagnosis using machine learning techniques. However, digital pathological images and related tasks have some issues to be considered. In this mini-review, we introduce the application of digital pathological image analysis using machine learning algorithms, address some problems specific to such analysis, and propose possible solutions.Comment: 23 pages, 4 figure

Artificial intelligence in cancer imaging: Clinical challenges and applications

Judgement, as one of the core tenets of medicine, relies upon the integration of multilayered data with nuanced decision making. Cancer offers a unique context for medical decisions given not only its variegated forms with evolution of disease but also the need to take into account the individual condition of patients, their ability to receive treatment, and their responses to treatment. Challenges remain in the accurate detection, characterization, and monitoring of cancers despite improved technologies. Radiographic assessment of disease most commonly relies upon visual evaluations, the interpretations of which may be augmented by advanced computational analyses. In particular, artificial intelligence (AI) promises to make great strides in the qualitative interpretation of cancer imaging by expert clinicians, including volumetric delineation of tumors over time, extrapolation of the tumor genotype and biological course from its radiographic phenotype, prediction of clinical outcome, and assessment of the impact of disease and treatment on adjacent organs. AI may automate processes in the initial interpretation of images and shift the clinical workflow of radiographic detection, management decisions on whether or not to administer an intervention, and subsequent observation to a yet to be envisioned paradigm. Here, the authors review the current state of AI as applied to medical imaging of cancer and describe advances in 4 tumor types (lung, brain, breast, and prostate) to illustrate how common clinical problems are being addressed. Although most studies evaluating AI applications in oncology to date have not been vigorously validated for reproducibility and generalizability, the results do highlight increasingly concerted efforts in pushing AI technology to clinical use and to impact future directions in cancer care

Preclinical performance of vaginal semisolid products: technological and safety evaluations assuming physiologic parameters

Vaginal semisolid products preclinical evaluations, when performed considering the particularities of the target organ, may represent key tools to predict in vivo performance. Before heading to clinical phases, vaginal semisolids must demonstrate to have an adequate technological and safety profile, in order to achieve higher success rates in the human testing stage. Traditional characterization methods currently used for vaginal semisolids do not undertake an integrative approach, since they do not address, for example, vaginal pH, fluid and temperature. Moreover, early safety assessment methods are largely described and validated not only on scientific literature, but also by regulatory agencies, although they are still mainly focused on cellular-based models. This safety profile of products can be further improved by combining toxicity testing, with drug release and permeation studies. Indeed, the vaginal administration route allows for local and systemic delivery of drugs, depending on the therapeutic purpose. Consequently, the drug should be confined to the chosen location of administration, to obtain maximum efficacy while avoiding side effects. The aim of this work was to develop a full set of assessment methods for characterization of vaginal semisolid products. Commercialized formulations were used to establish new methodological approaches that could be applied in new products development and characterization. Therefore, antimicrobials, Gino-canesten®, Sertopic®, Dermofix®, Gyno-pevaryl®, Lomexin®, Gino Travogen®, Dalacin V®; oestrogens, Ovestin®, Blissel® and Colpotrophine®; and, two reference formulations, Universal Placebo and Replens® were extensively evaluated. Technologically, they were tested in terms of pH, pH-buffering capacity, osmolality, textural parameters and viscosity, using a physiologic standpoint that considered the body temperature and dilution in a physiologic volume of vaginal fluid simulant (VFS); and even an ex vivo porcine model to infer bioadhesion and rheology on an after-administration environment. In terms of safety investigation, cellular toxicity was disclosed on VK2 E6/E7, HeLa and HEC-1A cell-lines, using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and NRU (Neutral Red Uptake) assays. Tissue explants, collected from the ex vivo porcine vaginal model, were also tested concerning toxicity, through MTT and histological analysis. Moreover, to include an advanced in vitro toxicity evaluation, the HET-CAM (Hen's Egg Test – Chorioallantoic Membrane), already in validation for eye irritation testing, was applied to vaginal irritation. A HPLC-DAD (High Performance Liquid Chromatography with Diode Array Detector) quantification method for the molecules present in semisolids included in this work, was developed and validated according to FDA (Food and Drug Administration - USA), EMA (European Medicines Agency) and ICH (International Conference for Harmonization) requirements. Further, this method was applied in drug quantification on in vitro drug release and ex vivo drug permeation experiments. These two techniques were performed using dynamic vertical Franz diffusion cells, having all experimental setting being specifically designed and optimized concerning the molecules in study (estriol, clotrimazole, econazole, isoconazole, sertaconazole and fenticonazole). Concerning technological characteristics, antimicrobial formulations exhibited lower pH than topical oestrogens. Buffering capacity in a vaginal fluid simulant conducted to better predictions of what happens in vivo. Characterization was performed also for those less acidic products to assess their ability to gain physiologic pH after mixing with simulated vaginal fluids. Products osmolality after dilution in VFS were below the upper limit advised by the World Health Organization (WHO). The antimicrobials had similar textural behaviours, while topical oestrogens varied in textural parameters. A slight decrease in viscosity was observed after application of dilution and temperature factors, showing the influence of the surrogate vaginal environment, while maintaining their pseudoplastic behaviour. However, each formulation had its own profile, possibly driven by their composition. Formulations’ viscosity was higher when tested using the ex vivo administration model than when only diluted in VFS at 37ºC. Concerning the in vitro models, VK2 E6/E7, presented relatively higher viabilities than HeLa and HEC-1A cells over the tested product concentrations. Tissue viability results were much higher than those obtained for the in vitro cellular models, revealing that this model could be more robust and closer to the in vivo situation. Across models, antimicrobials showed concentration-dependent viabilities. While oestrogens presented odd profiles, depending on the formulation and concentration tested. Reference products led to the most stable and higher viability profiles across concentrations. On ex vivo permeation studies we have investigated if there were differences in performing ex vivo permeation studies using the porcine vaginal model, when collecting a proximal or a distal tissue within the vaginal tube. No extensive significant differences between these tissues were found, but the caudal vagina could be more suitable for vaginal permeation experiments since it conducted to more reproducible and consistent results. Furthermore, it was observed that drug permeation is not directly dependent on drug release from the formulation. To sum up, the conduction of this integrative preclinical assessment for vaginal semisolids can be a valuable approach in new products development or characterisation, since it could optimize cost-efficiency of new formulations development by predicting in vivo efficacy and safety profiles. In addition, these methodologies have great potential not only to be applied in cosmetics, medical devices and medicines industry, but also in academical research.A avaliação pré-clínica de produtos semi-sólidos de administração vaginal quando é realizada tendo em consideração as particularidades intrínsecas desta via de administração, pode constituir-se como um ponto-chave na previsão do desempenho in vivo destes produtos. De facto, os medicamentos semi-sólidos vaginais são largamente prescritos e utilizados pelas mulheres, sendo também a classe de formas farmacêuticas de administração vaginal preferida por estas. Antes de entrarem nas fases clínicas do desenvolvimento, os semi-sólidos vaginais devem ter previamente demonstrado um perfil tecnológico adequado e devem ter dado provas de serem seguros. Deste modo, será possível obter maiores taxas de sucesso nas fases seguintes: pré-clínicas em animais (in vivo) e clínicas em humanos. Os métodos compendiais tradicionais de caracterização galénica e tecnológica não consideram as especificidades da via de administração vaginal, uma vez que não têm em conta, por exemplo, o pH vaginal, a composição e volume do fluido vaginal e a temperatura corporal. Além disso, mesmo na literatura científica é escassa a informação sistematizada de quais os parâmetros significativos a avaliar neste tipo de formulações. Avaliações precoces dos perfis de segurança e eficácia de medicamentos, são amplamente aconselhados, e, embora poucas, algumas estratégias e métodos encontram-se já descritas e validadas por agências reguladoras, contudo, concentram-se principalmente em modelos celulares. Adicionalmente, se por um lado a segurança pode ser abordada em testes de toxicidade, por outro, pode ainda ser mais amplamente caracterizada através da conjugação com resultados provenientes de estudos de libertação e permeação de fármacos. É um facto que a via de administração vaginal permite não só a administração de fármacos com vista a efeitos localizados, mas também efeitos sistémicos. Sendo que, uma ou outra pode ser desejada e a forma farmacêutica deve permitir que o fármaco seja confinado ao local de administração pretendido, para que se obtenha a máxima eficácia, evitando os efeitos secundários. O objetivo deste trabalho consistiu na realização de uma avaliação pré-clínica completa em formulações já comercializadas, a fim de estabelecer novas abordagens metodológicas que possam ser facilmente aplicadas no desenvolvimento e caracterização de novos produtos. Neste contexto, medicamentos semi-sólidos vaginais antimicrobianos, tais como, o Gino-canesten®, Sertopic®, Dermofix®, Gyno-pevaryl®, Lomexin®, Gino Travogen®, Dalacin V®; estrogénios, como o Ovestin®, Blissel® e Colpotrophine®; e ainda duas formulações de referência, o Placebo Universal e o Replens® foram amplamente avaliadas. Em termos tecnológicos foram testados o pH, a capacidade tampão, a osmolalidade, alguns parâmetros de textura e viscosidade, seguindo um ponto de vista fisiológico, em que se consideraram a temperatura corporal e a diluição num simulante de fluido vaginal (SFV). Foi ainda otimizado, um modelo vaginal suíno ex vivo para estudar estas formulações no que respeita à bioadesão e à reologia num ambiente pós-administração. Quanto ao estudo da segurança, a toxicidade celular foi avaliada nas linhas celulares: VK2 E6/E7 (vaginais), HeLa (cervicais) e HEC-1A (uterinas), e para tal, foram realizados os ensaios de viabilidade que utilizaram o MTT (brometo de 3-(4,5-dimetiltiazol-2-il)-2,5-difenil tetrazólio) e o NRU (captação de vermelho neutro). Além disso, tecidos epiteliais ex vivo, foram excisados a partir da vagina suína, e nestes, também foi aplicado o ensaio do MTT e, ainda uma análise histológica. Para incluir uma avaliação ainda mais avançada da toxicidade in vitro, os semi-sólidos vaginais foram testados num modelo organotípico: HET-CAM (ensaio que é realizado na membrana corio-alantóide de embriões de galinhas Henn) e que se encontra em validação para substituir o teste in vivo em animais para testes de irritação ocular. Deste modo, foi transposto este ensaio para a avaliação da irritação vaginal. Um método de quantificação de HPLC-DAD (Cromatografia Líquida de Alta Pressão acoplada a um detetor de díodos) para as moléculas presentes nos semi-sólidos vaginais incluídos neste trabalho, foi desenvolvido e validado de acordo com os requisitos das normas da FDA (Food and Drug Administration - EUA), da EMA (Agência Europeia de Medicamentos) e da ICH (Conferência Internacional para a Harmonização). Depois disso, este método foi aplicado na quantificação de fármacos nos estudos de libertação in vitro e nas experiências de permeação de fármacos ex vivo. Estas duas técnicas foram realizadas utilizando células de difusão dinâmicas verticais de Franz, tendo todas as configurações experimentais sido especificamente otimizadas para as moléculas em estudo (estriol, clotrimazol, econazole, isoconazol, sertaconazol e fenticonazol). Quanto às características tecnológicas, as formulações antimicrobianas apresentaram menor pH do que os estrogénios tópicos. A capacidade tampão no SFV conduziu a melhores previsões do que acontece in vivo. Após diluição em volumes fisiológicos de SFV, a osmolalidade da maioria dos produtos esteve conforme o recomendado pela Organização Mundial da Saúde (OMS), claramente dependente da composição. Os antimicrobianos apresentaram comportamentos de textura semelhantes entre eles, enquanto os estrogénios tópicos variaram entre eles, no que respeita aos parâmetros de textura. Com efeito, neste grupo encontrava-se uma formulação de base polimérica em gel (Blissel®), sendo que os restantes, eram cremes (Ovestin® e Colpotrophine). Regra geral, para todos os produtos observou-se uma ligeira diminuição da viscosidade após aplicação de fatores fisiológicos, como a diluição em SFV e a temperatura (37ºC), mas os seus comportamentos pseudoplásticos mantiveram-se. No entanto, cada formulação demonstrou ter o seu próprio perfil reológico, possivelmente conduzido pela sua composição, tanto qualitativa como quantitativa. Contudo, a viscosidade das formulações foi mais elevada quando testada num modelo de administração ex vivo, comparando com a viscosidade obtida nos ensaios em SFV a 37ºC. Este dado releva, que podem existir outros fatores determinantes na viscosidade adquirida após a administração de formulações semi-sólidas. Quanto aos modelos in vitro, as células VK2 E6/E7 apresentaram viabilidades relativamente superiores às células HeLa e HEC-1A nas concentrações de produto testadas. Os resultados de viabilidade no tecido foram muito superiores aos obtidos para nos modelos celulares. Isto revela que este modelo poderá ser mais robusto e mais próximo do que acontece in vivo. Em todos os modelos, as formulações antimicrobianas mostraram viabilidades dependentes da concentração. Ao contrário das formulações que contém estrogénios, que apresentaram perfis relacionados com os efeitos celulares estrogénicos reconhecidos (ou seja, foram dependentes da dosagem da formulação e da concentração testada). Os produtos de referência apresentaram os perfis de viabilidade mais estáveis e mais elevados em todas as concentrações. Nos estudos de permeação ex vivo, foi questionada a existência de diferenças na utilização de secções de tecido vaginal caudal ou cranial. Não obstante, em termos de permeação de fármacos, não foram encontradas extensas diferenças significativas entre estes dois tipos de epitélio, mas a vagina caudal parece ser mais adequada para experiências de permeação vaginal, uma vez que conduz a resultados mais reprodutíveis e consistentes. De facto, a região mais cranial da vagina suína apresenta, histologicamente, um epitélio mais fino, e anatomicamente, uma superfície que contém mais rugas. O que conduz a desvios-padrão entre experiências mais elevados. Além disso, observou-se que a permeação de fármacos não é apenas dependente da libertação do fármaco a partir formulação. A sua afinidade pela formulação e/ou pelo tecido, é determinante para a sua permeação até à câmara recetora. Concluindo, a avaliação pré-clínica integrada para semi-sólidos vaginais, proposta nesta tese, representa uma abordagem importante a ter em consideração, no desenvolvimento de novos produtos, uma vez que pode reduzir custos com o desenvolvimento de novas formulações, prevendo precocemente a sua eficácia in vivo e os seus perfis de segurança. Estas metodologias têm, assim, um grande potencial não só para serem aplicadas na indústria cosmética, farmacêutica e de dispositivos médicos, mas também pode ser aplicada em investigação mais fundamental ao nível da academia.The experimental work presented in this thesis was carried out at the Health Sciences Research Center laboratories, University of Beira Interior (CICS-UBI) and, at Labfit – Health Products Research and Development, Lda facilities

Optical techniques for 3D surface reconstruction in computer-assisted laparoscopic surgery

One of the main challenges for computer-assisted surgery (CAS) is to determine the intra-opera- tive morphology and motion of soft-tissues. This information is prerequisite to the registration of multi-modal patient-specific data for enhancing the surgeon’s navigation capabilites by observ- ing beyond exposed tissue surfaces and for providing intelligent control of robotic-assisted in- struments. In minimally invasive surgery (MIS), optical techniques are an increasingly attractive approach for in vivo 3D reconstruction of the soft-tissue surface geometry. This paper reviews the state-of-the-art methods for optical intra-operative 3D reconstruction in laparoscopic surgery and discusses the technical challenges and future perspectives towards clinical translation. With the recent paradigm shift of surgical practice towards MIS and new developments in 3D opti- cal imaging, this is a timely discussion about technologies that could facilitate complex CAS procedures in dynamic and deformable anatomical regions

Pharma-engineering of multifunctional microneedle array device for application in chronic pain

Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within this thesis is the possibility of further developing transdermal drug delivery for chronic pain treatment using an Electro-Modulated Hydrogel- Microneedle array (EMHM) prototype device for the delivery of analgesic medicatio

Simulation of Clinical PET Studies for the Assessment of Quantification Methods

On this PhD thesis we developed a methodology for evaluating the robustness of SUV measurements based on MC simulations and the generation of novel databases of simulated studies based on digital anthropomorphic phantoms. This methodology has been applied to different problems related to quantification that were not previously addressed. Two methods for estimating the extravasated dose were proposed andvalidated in different scenarios using MC simulations. We studied the impact of noise and low counting in the accuracy and repeatability of three commonly used SUV metrics (SUVmax, SUVmean and SUV50). The same model was used to study the effect of physiological muscular uptake variations on the quantification of FDG-PET studies. Finally, our MC models were applied to simulate 18F-fluorocholine (FCH) studies. The aim was to study the effect of spill-in counts from neighbouring regions on the quantification of small regions close to high activity extended sources

Perfusion MRI quantification for Multi-Echo EPIK sequence in brain tumour patients

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Engenharia Clínica e Instrumentação Médica) Universidade de Lisboa, Faculdade de Ciências, 2018The main goal of this thesis was to obtain fully quantifying perfusion parameters from both DSC (Dy-namic Susceptibility Contrast) and DCE (Dynamic Contrast Enhancement) techniques through usage of only one perfusion sequence–GESEEPIK (Gradient-echo, Spin-echo Echo-Planar Imaging with Key- hole). For this, twenty-two patients with a possible brain tumor were recruited for this study, and each patient was scanned data hybrid PET-MR 3T scanner. Firstly, T1-mapping data was acquired through a sequence of Inversion-Recovery EPIK. The contrast agent was then injected into the patient and perfusion images were acquired using the GESE EPIK sequence. Simultaneously, 18F-FET images were acquired which allowed the exclusion of patients who did not have any brain tumor. After the images were acquired, they were analyzed and the parameters were calculated. For starters, the information regarding the changes in T2 and T2*, already inherent to the data acquired, was analyzed. The curve of the MR signal was converted to the concentration curve. This curve was calculated using two different equations. With the calculated concentration curve, the DSC parameters were calculated. As expected, in areas affected by a tumor, there was an increase in vascularization due to angiogenesis. It was also observed, by comparison of the two methods used to calculate the concentration curves, that the non-removal of the leakage effects induced an unreal increase in the calculated parameters. In order to obtain images related to variations of T1 for DCE quantification, the images acquired were extrapolated to a echo time equal to zero. To these extrapolated images, the values obtained from the T1-mapping prior to the contrast’s injection were subtracted in order to obtain the concentration curve. A method that used the extrapolated images to obtain an initial T1-mapping was also tested, in order to avoid the need to implement the extra sequence for that purpose. The tofts kinetic model was applied in both methods, allowing the calculation of DCE parameters. In both applied methods, the results obtained were very similar, indicating the possibility of non-acquisition of the extra sequence if there are time constraints. However, not all parameters behaved as expected and a more detailed investigation of the literature was carried out. It is concluded that some parameters do not have a clear description and cannot characterize human physiology and be used in the study of pathologies. In conclusion, the initial goal of this thesis to obtain quantitative parameters DSC and DCE perfusion techniques, using only a single contrast sequence, was achieved with success. The need to remove leak age effects, which increased the calculated values and the tumor area, was also verified. However, some inconsistencies in the parameters’ interpretation were registered in the available literature. These inconsistencies had repercussions in some values obtained, whose interpretation was impossible, despite being in agreement with the literature. In addition, a method has been tested which further eliminates the need to acquireT1-mapping data prior to the contrast’s injection through an addition al sequence. Although not an objective of this thesis, It was not possible to relate the perfusion parameters to the degree of tumor severity

Quantitative Imaging in Electron and Confocal Microscopies for Applications in Biology

Among the large number of topics related to the quantification of images in electron and confocal microscopies for applications in biology, we selected four subjects that we consider to be representative of some recent tendencies. The first is the quantification of three-dimensional data sets recorded routinely in scanning confocal microscopy. The second is the quantification of the textural and fractal appearance of images. The two other topics are related to image series, which are more and more often provided by imaging instruments. The first kind of series concerns electron energy-filtered images. We show that the parametric (modelling) approach can be complemented by non-parametric approaches (e.g., different variants of multivariate statistical techniques). The other kind of series consists of multiple mappings of a specimen. We describe several new tools for the study and quantification of the co-location, with potential application to multiple mappings in microanalysis or in fluorescence microscopy

CT based radiomic approach on first line pembrolizumab in lung cancer

Clinical evaluation poorly predicts outcomes in lung cancer treated with immunotherapy. The aim of the study is to assess whether CT-derived texture parameters can predict overall survival (OS) and progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) treated with first line Pembrolizumab. Twenty-one patients with NSLC were prospectively enrolled; they underwent contrast enhanced CT (CECT) at baseline and during Pembrolizumab treatment. Response to therapy was assessed both with clinical and iRECIST criteria. Two radiologists drew a volume of interest of the tumor at baseline CECT, extracting several texture parameters. ROC curves, a univariate Kaplan-Meyer analysis and Cox proportional analysis were performed to evaluate the prognostic value of texture analysis. Twelve (57%) patients showed partial response to therapy while nine (43%) had confirmed progressive disease. Among texture parameters, mean value of positive pixels (MPP) at fine and medium filters showed an AUC of 72% and 74% respectively (P < 0.001). Kaplan-Meyer analysis showed that MPP < 56.2 were significantly associated with lower OS and PFS (P < 0.0035). Cox proportional analysis showed a significant correlation between MPP4 and OS (P = 0.0038; HR = 0.89[CI 95%:0.83,0.96]). In conclusion, MPP could be used as predictive imaging biomarkers of OS and PFS in patients with NSLC with first line immune treatment

Inflammatory dependent bioresponsive smart transdermal delivery system incorporating susppended nanofibrous mats as a platform for wound healing

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, South Africa Johannesburg 2016The perception of wound healing within the current decade goes beyond the straightforward assertion of the three phases assembling the wound healing cascade. Healing of wounds is a complex process that involves a dynamic series of interactions and reactions and requires a collaboration of the many cell pedigrees, mediators and different tissues. The skin is the largest organ of the body and serves as a protective barrier against foreign objects therefore a loss in its veracity may lead to a decrease quality of life or even death. The primary goal for wound care and treatment is an aesthetically pleasing scar with close to complete functionality at the wound site and rapid wound closure. Attainment of these features requires incorporation of various characteristics such as a moisture retention, absorption and debridgement amongst others. A huge variety of wound dressings are available however not all of these meet the specific requirements of an ideal wound healing device to cover every aspect within the wound healing cascade. Highlighted within this thesis is the design and development of a Bioresponsive transdermal delivery system (BTDS) for wound healing that aims at the incorporation of the significant characteristics for optimal wound management and treatment. Nanobiotechnology is an interdisciplinary field that combines many avenues to revolutionise the development of drug delivery systems specific to wound healing. Delivery systems produced on the nanoscale can encourage the promotion of biologically active new molecular entities that were previously considered underdeveloped by the enhancement of the therapeutic efficacy of wound healing materials. Recent research interest has focused on the development of smart biomaterials. Combining biomaterials that are crucial for wound healing will provide opportunities to synthesize matrices that are inductive to cells and that stimulate and trigger target cell responses crucial to the wound healing process. Stimuli responsive systems provides an attractive, novel and alternate approach to the process of healing by offering an advanced alternative to simple wound dressings as they have the ability to adapt to the surrounding wound environment and regulate the healing process by thermal, chemical, biochemical, electrical and mechanical means on exposure to an external stimulus that triggers the effect. The research focused on the development and characteristic analysis of a complete prototyped device for wound healing incorporating a nanofibrous mat as well as a bioresponsive component to inflammation which could be the first novel prototype developed as an inflammation bioresponsive device for superior wound healing incorporating a nanofibrous mat. The BTDS was synthesized by the attainment of a statistically derived Box- Behnken Design Template, whereby 15 formulations were generated to fabricate a wound healing nanofibrous mats as well as a lyophilized inflammatory dependent matrix. The technique entailed the process of electrospinning for nanofiber formation as well as blending and lyophilization for the inflammatory responsive component. Elucidation of the various polymeric and crosslinker concentrations greatly influenced the properties and characteristics of the system. An endorsement in intensity and conjugation is noted by the FTIR spectra whereby greater shifts in wavelengths from 3260.11cm-1 to 3278.79cm-1 is noted when enhancements in crosslinking bridges is undertaken. Structural morphological analysis revealed the synthesis of smooth, cylindrical, uniformly aligned nanofibres without the presence of nanobeads as well as the formation of a lyophilized matrix having a tough backbone structure at higher concentrations. Upon nanotensile mapping, variation in Young‟s Modulus was observed at 4.25MPa providing flexibility whereas a higher Young‟s Modulus provides rigidity and stiffness to the structure. Determination of the bioresponsive nature was carried out in a stimulated inflammatory environment by utilisation of the Fentons reaction: Fe2+ + H2O2 → Fe3+ + OH∙ + OH- . Results amongst the experimentally derived formulations revealed the reliance of bioactive release on the hyaluronic acid concentration and degradation by hydroxyl radicals present. MDT results obtained depicted a value at 42.39 at a higher hyaluronic concentration and degree of crosslinkage whereas at lower concentrations, MDT values at 33.21 and 35.76 were depicted. In vivo histological examination revealed the healing progression whereby the presence of the nanofibrous mat illucidated a close to complete re-epithelisation and remodelling of the wound site represented by thick, vascular granulation tissue dominated by fibroblasts and extensive collagen deposition. The approach of introducing a topical device for wound management containing both nanotechnology and stimuli responsive techniques provide an innovative and encouraging proposal for wound care to the pharmaceutical industry.MT201