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Michelle Griffin,1–3 Robert Palgrave,4 Víctor G Baldovino-Medrano,5 Peter E Butler,1–3 Deepak M Kalaskar1,6 1UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, London, UK; 2Royal Free London NHS Foundation Trust Hospital, London, UK; 3The Charles Wolfson Center for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, UK; 4Department of Chemistry, University College London, London, UK; 5Laboratory of Surface Science (SurfLab), School of Chemical Engineering, Piedecuesta, Colombia; 6UCL Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, London, UK Background: Tissue integration and vessel formation are important criteria for the successful implantation of synthetic biomaterials for subcutaneous implantation. Objective: We report the optimization of plasma surface modification (PSM) using argon (Ar), oxygen (O2) and nitrogen (N2) gases of a polyurethane polymer to enhance tissue integration and angiogenesis. Methods: The scaffold’s bulk and surface characteristics were compared before and after PSM with either Ar, O2 and N2. The viability and adhesion of human dermal fibroblasts (HDFs) on the modified scaffolds were compared. The formation of extracellular matrix by the HDFs on the modified scaffolds was evaluated. Scaffolds were subcutaneously implanted in a mouse model for 3 months to analyze tissue integration, angiogenesis and capsule formation. Results: Surface analysis demonstrated that interfacial modification (chemistry, topography and wettability) achieved by PSM is unique and varies according to the gas used. O2 plasma led to extensive changes in interfacial properties, whereas Ar treatment caused moderate changes. N2 plasma caused the least effect on surface chemistry of the polymer. PSM-treated scaffolds significantly (P

Griffin M, Palgrave R, Baldovino-Medrano VG, et al. Int J Nanomedicine. 2018;13:6123–6141.On page 6123, Víctor G Baldovino-Medrano’s affiliation details were incorrectly listed as follow:Michelle Griffin1–3Robert Palgrave4Víctor G Baldovino-Medrano5Peter E Butler1–3Deepak M Kalaskar1,61UCL Centre for Nanotechnology and Regenerative edicine, Division of Surgery and Interventional Science, University College London, London, UK; 2Royal Free London NHS Foundation Trust Hospital, London, UK; 3The Charles Wolfson Center for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, UK; 4Department of Chemistry, University College London, London, UK; 5Laboratory of Surface Science (SurfLab), School of Chemical Engineering, Piedecuesta, Colombia; 6UCL Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, London, UK The corrected author list and affiliation details are as follow:Michelle Griffin1–3Robert Palgrave4Víctor G Baldovino-Medrano5–7Peter E Butler1–3Deepak M Kalaskar1,81UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, London, UK; 2Royal Free London NHSHS Foundation Trust Hospital, London, UK; 3The Charles Wolfson Center for Reconstructive Surgery, Royal Free London NHSHS Foundation Trust Hospital, ondon, UK; 4Department of Chemistry, University College London, London, UK; 5Centro de Materiales y anociencias CMN), 6Centro de Investigaciones en Catálisis (CICAT), 7Laboratorio de Ciencia de Superficies (SurfLab), Escuela de Ingeniería Química, Universidad Industrial de Santander, Piedecuesta (Santander) 681011, Colombia; 8UCL institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, London, UK. Read the original article

Purpose: The study conducts a comparative analysis between two prominent methods for fabricating composites for bone scaffolds-the (solid) solvent method and the solvent-free (melting) method. While previous research has explored these methods individually, this study provides a direct comparison of their outcomes in terms of physicochemical properties, cytocompatibility, and mechanical strength. We also analyse their workflow and scalability potentials., Design/methodology/approach: Polycaprolactone (PCL) and hydroxyapatite (HA) composites were prepared using solvent (chloroform) and melting (180°C) methods, then 3D-printed using an extrusion-based 3D printer to fabricate scaffolds (8 × 8 × 4 mm). Rheology, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), accelerated degradation, mechanical/compression test, wettability/contact angle, live/dead assay, and DNA quantification (Picogreen) assays were evaluated., Findings: The study finds that scaffolds made via the solid solvent method have higher mechanical strength and degradation rate as compared to those from the melting method, while both methods ensure adequate cytocompatibility and homogenous hydroxyapatite distribution, supporting their use in bone tissue engineering., Originality: This research investigates the utility of chloroform as a solvent for PCL composite in a direct comparison with the melting method. It also highlights the differences in workflows between the two methods and their scalability implications, emphasizing the importance of considering workflow efficiency and the potential for automation in scaffold fabrication processes for bone tissue engineering applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 De Vega, Dutta, Mumtaz, Schroeder, Gerrand, Boyd and Kalaskar.)

Pedicled, fasciocutaneous and visceral flaps are all widely adopted for reconstruction after ablative surgery for advanced laryngeal, hypopharyngeal and cervical oesophageal cancers. With multiple options available, the choice depends on type and extent of the defect, patient's general conditions and institution expertise or preference. Since its first description in 1959, the use of jejunal free flap (JFF) has been refined thanks to the introduction of microvascular anastomoses, progressively allowing to achieve low mortality and morbidity rates. Both swallowing and speech outcomes are also positively reported across studies. A systematic review of English literature on JFF in H&N cancer reconstruction published after 2000 was carried out on Medline and Embase. Thirty-six studies were included in the analysis with a total of 3191 JFF reconstructions. Primary outcomes were surgical complications and functional outcomes (quality of speech and oral alimentation). A cumulative review was created pooling complication rates reported in single studies, and overall rates were obtained for fistulas (11.39%), strictures (14.17%), total and partial flap failure (4.79 and 6.15% respectively) and perioperative mortality (3.1%). Functional outcomes were variably reported, with different qualitative and quantitative assessment methods showing overall positive results. When reported, we've included impact of adjuvant radiotherapy and the ability of JFF to tolerate it has been widely confirmed. Above results have also been compared with same outcomes registered for different flaps. Overall, studies over the past 20 years demonstrate good clinical and functional outcomes, proving JFF to be a reliable and safe method for reconstructing circumferential pharyngoesophageal defects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: This study compares the precision, accuracy, and user experience of 3D body surface scanning of human subjects using the Artec Leo hand-held scanner and the iPad Pro as 3D scanning devices for capturing cervical and craniofacial data. The investigation includes assessing methods for correcting 'dropped head syndrome' during scanning, to demonstrate the ability of the scanner to be used to reconstruct body surface of patients., Methods: Eighteen volunteers with no prior history of neck weakness were scanned three times in three different positions, using the two different devices. Surface area, scanning time, and participant comfort scores were evaluated for both devices. Precision and accuracy were assessed using Mean Absolute Deviation (MAD), Mean Absolute Percentage Error (MAPE), and Intra-Class Correlation Coefficients (ICC)., Results: Surface area comparisons revealed no significant differences between devices and positions. Scanning times showed no significant difference between devices or positions. Comfort scores varied across positions. MAD analysis identified chin to chest measurements as having the highest variance, especially in scanning position 3. However, no statistical differences were found. MAPE results confirmed accuracy below 5% error for both devices. ICC scores indicated good reliability for both measurement methods, particularly for chin to chest measurements in positions 1 and 3., Conclusion: The iPad Pro using the Qlone app demonstrates a viable alternative to the Artec Leo, particularly for capturing head and neck surface area within a clinical setting. The scanning resolution, with an error margin within ±5%, is consistent with clinically accepted standards for orthosis design, where padding and final fit adjustments allow for bespoke devices that accommodate patient comfort. This study highlights the comparative performance of the iPad, as well as suggests two methods which can be used within clinics to correct head drop for scanning., Competing Interests: Declarations. Ethics approval and consent to participate: UCL Research Ethics Committee approval (20583/001), written consent was obtained for each participant. Consent for publication: All Authors provided consent for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Motor Neurone Disease (MND), is a debilitating neurodegenerative condition, which significantly impacts the quality of life of those affected. Neck weakness is one challenge faced by those living with MND and as such may require a neck collar to assist. However, the user experience and requirements related to these neck collars have not been comprehensively explored. Understanding these priorities is crucial for enhancing the well-being of MND patients., Objective: To understand the priorities of people living with Motor Neurone Disease (MND) including user experience, requirements and the importance of neck collars used to aid neck weakness., Methods: An online survey was used to investigate the perspectives and experiences of off the shelf neck collars used by people living with MND. The MND Association was selected as a strategic partner by their affiliations and access to large data base of MND patients., Results: Survey highlighted a disparity between the actual duration MND patients wear their current neck collars and their desired duration, emphasising the need to integrate collars into daily activities. Key areas for improvement with existing neck collars centred on comfort and reduced restriction, with respondents expressing a preference for collars that offer support without impeding movement. Additionally, addressing pressure on the anterior neck region during collar use emerged as a critical requirement., Conclusion: Current collars do not cause any clinical complications; however, they do fall short of meeting the expected needs of people living with MND, including discomfort, restricted movement, and pressure to the anterior region of the neck. This study highlights need to improve current collar designs to provide better quality of life for MND patients., Competing Interests: Declaration of competing interest NS is CEO & co-founder of BioCorteX Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic skin wounds pose a global clinical challenge, necessitating effective treatment strategies. This study explores the potential of 3D printed Poly Lactic Acid (PLA) scaffolds, enhanced with Whey Protein Concentrate (WPC) at varying concentrations (25, 35, and 50% wt), for wound healing applications. PLA's biocompatibility, biodegradability, and thermal stability make it an ideal material for medical applications. The addition of WPC aims to mimic the skin's extracellular matrix and enhance the bioactivity of the PLA scaffolds. Fourier Transform Infrared Spectroscopy results confirmed the successful loading of WPC into the 3D printed PLA-based scaffolds. Scanning Electron Microscopy (SEM) images revealed no significant differences in pore size between PLA/WPC scaffolds and pure PLA scaffolds. Mechanical strength tests showed similar tensile strength between pure PLA and PLA with 50% WPC scaffolds. However, scaffolds with lower WPC concentrations displayed reduced tensile strength. Notably, all PLA/WPC scaffolds exhibited increased strain at break compared to pure PLA. Swelling capacity was highest in PLA with 25% WPC, approximately 130% higher than pure PLA. Scaffolds with higher WPC concentrations also showed increased swelling and degradation rates. Drug release was found to be prolonged with increasing WPC concentration. After seven days of incubation, cell viability significantly increased in PLA with 50% WPC scaffolds compared to pure PLA scaffolds. This innovative approach could pave the way for personalized wound care strategies, offering tailored treatments and targeted drug delivery. However, further studies are needed to optimize the properties of these scaffolds and validate their effectiveness in clinical settings., (Creative Commons Attribution license.)

Background: Targeted nanoparticles (NPs) are aimed at improving clinical outcomes by enhancing the diagnostic and therapeutic efficacy of drugs in the treatment of Alzheimer's disease (AD)., Methods: Curcumin (CUR)-loaded poly-lactic-co-glycolic acid (PLGA) NPs (CNPs) were produced to demonstrate a prolonged release and successfully embedded into 3D printed sodium alginate (SA)/gelatin (GEL) scaffolds that can dissolve rapidly sublingually. Characterization and in vitro activity of the NPs and scaffolds were evaluated., Results: Based on the in vitro drug release studies, 99.6 % of the encapsulated CUR was released in a controlled manner within 18 days for the CNPs. In vitro cell culture studies showed that all samples exhibited cell viability above 84.2 % and no significant cytotoxic effect on SH-SY5Y cells. The samples were analyzed through 2 different pathways by PCR analysis. Real-time PCR results indicated that CNP and CNP-embedded SA/GEL scaffolds (CNPSGS) may show neuroprotective effects by modulating the Wnt/β-catenin pathway. The gene expression level of β-catenin slightly increased compared to the gene expression levels of other proteins and enzymes with these treatments. However, the PI3K/Akt/GSK-3β signaling pathway was regulated at the same time because of the crosstalk between these 2 pathways., Conclusion: CNPSGS might be an effective therapeutic alternative for AD treatment., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a neurodegeneration type that is biologically recognizable via β-amyloid plaques and tau neurofibril tangles. Global estimation for the total count of individuals enduring AD will rise up to 131 million by 2050. Investigations suggested the existence of a direct proportion between the likelihood of AD occurrence and vitamin B 12 (VB 12 ) hypovitaminosis. Approved VB 12 administrations, intramuscular and oral, each has serious defects broaching the demand for alternative routes. This work developed VB 12 -loaded chitosan/tripolyphosphate/polyvinyl alcohol (CS/TPP/PVA) nanoparticles (NPs) embedded in polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone/polycaprolactone (PVP/PCL) nanofibrous (NFs) produced by pressurized gyration (PG) for sublingual and transdermal routes, respectively. Biomaterials were investigated morphologically, chemically, and thermally. Moreover, degradation, disintegration, release behavior, and release kinetics were analyzed. The effectiveness and safety of nanomaterials were assessed and proven with the alamarBlue test on the Aβ 1-42 -induced SH-SY5Y model. The final evaluation suggested the feasibility, safety, and effectiveness of produced systems. Consequently, two alternative VB 12 application routes were developed with high effectivity and low toxicity with the power of nanotechnology., Competing Interests: Declaration of competing interest The authors all declare that there is no existing conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Silk has been consistently popular throughout human history due to its enigmatic properties. Today, it continues to be widely utilized as a polymer, having first been introduced to the textile industry. Furthermore, the health sector has also integrated silk. The Bombyx mori silk fibroin (SF) holds the record for being the most sustainable, functional, biocompatible, and easily produced type among all available SF sources. SF is a biopolymer approved by the FDA due to its high biocompatibility. It is versatile and can be used in various fields, as it is non-toxic and has no allergenic effects. Additionally, it enhances cell adhesion, adaptation, and proliferation. The use of SF has increased due to the rapid advancement in tissue engineering. This review comprises an introduction to SF and an assessment of the relevant literature using various methods and techniques to enhance the tissue engineering of SF-based hydrogels. Consequently, the function of SF in skin tissue engineering, wound repair, bone tissue engineering, cartilage tissue engineering, and drug delivery systems is therefore analysed. The potential future applications of this functional biopolymer for biomedical engineering are also explored.

Epilepsy is a medical condition that causes seizures and impairs the mental and physical activities of patients. Unfortunately, over one-third of patients do not receive adequate relief from oral Antiepileptic Drugs (AEDs) and continue to experience seizures. In addition to that, long term usage of Antiepileptic Drugs can cause a range of side effects. To overcome this problem, the precision of 3D printing technology is combined with the controlled release capabilities of biodegradable polymers, allowing for tailored and localized AED delivery to specific seizure sites. As a result of this novel technique, therapeutic outcomes can be enhanced, side effects of AEDs are minimized, and patient-specific dosage forms can be created. This study focused on the use of ethosuximide, an antiepileptic drug, at different concentrations (10, 13, and 15 mg) loaded into 3D-printed sodium alginate and polyethylene oxide scaffolds. The scaffolds contained varying concentrations (0.25%, 0.50%, and 0.75% w/v) and had varying pores created by 3D patterning sizes from 159.86 ± 19.9 µm to 240.29 ± 10.7 µm to optimize the releasing system for an intracranial administration. The addition of PEO changed the T g and T m temperatures from 65°C to 69°C and from 262°C to 267°C, respectively. Cytotoxicity assays using the human neuroblastoma cell line (SH-SY5Y) showed that cell metabolic activity reached 130% after 168 h, allowing the cells to develop into mature neural cells. In vitro testing demonstrated sustained ethosuximide release lasting 2 hours despite crosslinking with 3% CaCl 2 . The workpaves the way for the use of ethosuximide -loaded scaffolds for treating epilepsy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Karabulut, Dutta, Moukbil, Cisen Akyol, Ulag, Aydin, Gulhan, Us, Kalaskar and Gunduz.)

Cardiovascular diseases continue to be a major contributor to illness and death on a global scale, and the implementation of stents has given rise to a revolutionary transformation in the field of interventional cardiology. The thrombotic and restenosis complications associated with stent implantation pose ongoing challenges. In recent years, bioactive coatings have emerged as a promising strategy to enhance stent hemocompatibility and reduce thrombogenicity. This review article provides an overview of the surface engineering techniques employed to improve the hemocompatibility of stents and reduce thrombus formation. It explores the mechanisms underlying thrombosis and discusses the factors influencing platelet activation and fibrin formation on stent surfaces. Various bioactive coatings, including anticoagulant agents, antiplatelet agents, and surface modifications, are discussed in detail, highlighting their potential in reducing thrombogenicity. This article also highlights a multitude of surface modification techniques which can be harnessed to enhance stent hemocompatibility including plasma treatment, physical vapor deposition (PVD), chemical vapor deposition (CVD), and electrodeposition. These techniques offer precise control over surface properties such as roughness, charge, and composition. The ultimate goal is to reduce platelet adhesion, tailor wettability, or facilitate the controlled release of bioactive agents. Evaluation methods for assessing hemocompatibility and thrombogenicity are also reviewed, ranging from in vitro assays to animal models. Recent advances in the field, such as nanotechnology-based coatings and bioactive coatings with controlled drug release systems, are highlighted. Surface engineering of bioactive coatings holds great promise for enhancing the long-term outcomes of stent implantation by enhancing hemocompatibility and reducing thrombogenicity. Future research directions and potential clinical applications are discussed, underscoring the need for continued advancements in this field.

The recent advancement in the human glycome and progress in the development of an inclusive network of glycosylation pathways allow the incorporation of suitable machinery for protein modification in non-natural hosts and explore novel opportunities for constructing next-generation tailored glycans and glycoconjugates. Fortunately, the emerging field of bacterial metabolic engineering has enabled the production of tailored biopolymers by harnessing living microbial factories (prokaryotes) as whole-cell biocatalysts. Microbial catalysts offer sophisticated means to develop a variety of valuable polysaccharides in bulk quantities for practical clinical applications. Glycans production through this technique is highly efficient and cost-effective, as it does not involve expensive initial materials. Metabolic glycoengineering primarily focuses on utilizing small metabolite molecules to alter biosynthetic pathways, optimization of cellular processes for glycan and glycoconjugate production, characteristic to a specific organism to produce interest tailored glycans in microbes, using preferably cheap and simple substrate. However, metabolic engineering faces one of the unique challenges, such as the need for an enzyme to catalyze desired substrate conversion when natural native substrates are already present. So, in metabolic engineering, such challenges are evaluated, and different strategies have been developed to overcome them. The generation of glycans and glycoconjugates via metabolic intermediate pathways can still be supported by glycol modeling achieved through metabolic engineering. It is evident that modern glycans engineering requires adoption of improved strain engineering strategies for creating competent glycoprotein expression platforms in bacterial hosts, in the future. These strategies include logically designing and introducing orthogonal glycosylation pathways, identifying metabolic engineering targets at the genome level, and strategically improving pathway performance (for example, through genetic modification of pathway enzymes). Here, we highlight current strategies, applications, and recent progress in metabolic engineering for producing high-value tailored glycans and their applications in biotherapeutics and diagnostics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Approximately one quarter of women are affected by asymmetry as a result of abnormal breast development, which can lead to significant emotional distress. Despite this, there is currently no widely accepted approach for managing this prevalent condition. This systematic review aimed to review the available literature on the management of developmental breast asymmetry., Methods: A comprehensive search in MEDLINE, EMBASE, and CENTRAL databases was conducted for primary clinical studies reporting on the management of developmental breast asymmetry from 1962 to November 2022. The primary outcome measures were long-term aesthetic outcomes and patient-reported outcomes., Results: Eleven case series and 2 cohort studies were included, comprising a total of 1237 patients with a mean age of 26.5 years (range 14-65 years). Twelve studies (92%) addressed asymmetry through surgical means, using various augmentation and reduction procedures, whereas one study (8%) utilized external prostheses. Meta-analysis of the data was not deemed to be possible because of heterogeneity of data; a narrative synthesis of the literature was provided., Conclusions: There is no consensus on how to manage developmental breast asymmetry. Furthermore, there is a lack of consistency in the classification of patients with developmental breast asymmetry and in the reporting of outcomes, highlighting the need for a consensus. Further research outlining long-term aesthetic and patient-reported outcomes is needed to understand which procedures provide optimal outcomes. In addition, external breast prosthesis is a promising nonsurgical alternative, and further studies into its efficacy are needed., Competing Interests: Declaration of Competing Interest None., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Adolescent idiopathic scoliosis (AIS) is a noticeable spinal deformity in both adult and adolescent population. In majority of the cases, the gold standard of treatment is surgical intervention. Technological advancements in medical imaging and 3D printing have revolutionised the surgical planning and intraoperative decision making for surgeons in spinal surgery. However, its applicability for planning complex spinal surgeries is poorly documented with human subjects. The objective of this study is to evaluate the accuracy of 3D printed models for complex spinal deformities based on Cobb angles between 40° to 95°.This is a retrospective cohort study where, five CT scans of the patients with AIS were segmented and 3D printed for evaluating the accuracy. Consideration was given to the Inter-patient and acquisition apparatus variability of the CT-scan dataset to understand the effect on trueness and accuracy of the developed CAD models. The developed anatomical models were re-scanned for analysing quantitative surface deviation to assess the accuracy of 3D printed spinal models. Results show that the average of the root mean square error (RMSE) between the 3DP models and virtual models developed using CT scan of mean surface deviations for the five 3d printed models was found to be 0.5±0.07 mm. Based on the RMSE, it can be concluded that 3D printing based workflow is accurate enough to be used for presurgical planning for complex adolescent spinal deformities. Image acquisition and post processing parameters, type of 3D printing technology plays key role in acquiring required accuracy for surgical applications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

In the modern world, animal and plant protein may not meet the sustainability criteria due to their high need for arable land and potable water consumption, among other practices. Considering the growing population and food shortage, finding alternative protein sources for human consumption is an urgent issue that needs to be solved, especially in developing countries. In this context, microbial bioconversion of valuable materials in nutritious microbial cells represent a sustainable alternative to the food chain. Microbial protein, also known as single-cell protein (SCP), consist of algae biomass, fungi or bacteria that are currently used as food source for both humans and animals. Besides contributing as a sustainable source of protein to feed the world, producing SCP, is important to reduce waste disposal problems and production costs meeting the sustainable development goals. However, for microbial protein as feed or food to become an important and sustainable alternative, addressing the challenges of raising awareness and achieving wider public regulatory acceptance is real and must be addressed with care and convenience. In this work, we critically reviewed the potential technologies for microbial protein production, its benefits, safety, and limitations associated with its uses, and perspectives for broader large-scale implementation. We argue that the information documented in this manuscript will assist in developing microbial meat as a major protein source for the vegan world., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Empagliflozin (EM) was successfully loaded in polycaprolactone/poly (L-lactic acid)/polymethyl methacrylate (PCL/PLA/PMMA) fibers. In the rat β-cell line (BRIN-BD11), the insulin expression ratio of pancreatic β-cells was stimulated at high and low glucose by culturing with tri-layer EM-loaded fiber (EMF) for 48 h. The expression ratios of glucokinase and GLUT-2 proteins increased after EMF treatment. According to the in vitro drug release test, 97% of all drug contained in fibers was released in a controlled manner for 24 h. The pharmacokinetic test revealed that the bioavailability was improved ∼4.8-fold with EMF treatment compared to EM-powder and blood glucose level was effectively controlled for 24 h with EMF. Oral administration of EMF exhibited a better sustainable anti-diabetic activity even in the half-dosage than EM-powder in streptozotocin/nicotinamide-induced T2DM rats. The levels of GLP-1, PPAR-γ, and insulin were increased while the levels of SGLT-2 and TNF-α were decreased with EMF treatment. Also, EMF recovered the histopathological changes in the liver, pancreas, and kidney in T2DM rats and protected pancreatic β-cells. Consequently, EMF is suggested as an unprecedented and promotive treatment approach for T2DM with a higher bioavailability and better antidiabetic effect compared to conventional dosage forms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A majority of people living with motor neuron disease (MND) experience weakness of the neck and as a result, experience head drop. This exacerbates problems with everyday activities (eating, talking, breathing, etc). Neck collars are often used to support head drop; however, these are typically designed for prehospitalization settings to manage and brace the cervical region of the spine. As a result, it has been recorded that people living with MND often reject these collars for a variety of reasons but most notably because they are too restricting. The current standardized outcome measures (most notably restricting cervical range of motion) used for neck collars are summarized herein along with whether they are suitable for a bespoke neck collar specifically designed for people living with MND., (©Samuel D J Spears, Yusuf F Abdulle, Dionisios Korovilas, Ryo Torii, Deepak M Kalaskar, Nikhil Sharma. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 14.03.2023.)

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by impaired insulin secretion, sensitivity, and hyperglycemia. Diabetic wounds are one of the significant complications of T2DM owing to its difficulty in normal healing, resulting in chronic wounds. In the present work, PCL/PVA, PCL/PVA/PCL, and metformin-loaded, PCL/PVA-Met and PCL/PVA-Met/PCL hybrid scaffolds with different designs were fabricated using 3D printing. The porosity and morphological analysis of 3D-printed scaffolds were performed using scanning electron microscopy (SEM). The scaffolds' average pore sizes were between 63.6 ± 4.0 and 112.9 ± 3.0 μm. Molecular and chemical interactions between polymers and the drug were investigated with Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). Mechanical, thermal, and degradation analysis of the scaffolds were undertaken to investigate the physico-chemical characteristics of the scaffolds. Owing to the structure, PCL/PVA/PCL sandwich scaffolds had lower degradation rates than the bi-layer scaffolds. The drug release of the metformin-loaded scaffolds was evaluated with UV spectrometry, and the biocompatibility of the scaffolds on fibroblast cells was determined by cell culture analysis. The drug release in the PCL/PVA-Met scaffold was sustained till six days, whereas in the PCL/PVA-Met/PCL, it continued for 31 days. In the study of drug release kinetics, PCL/PVA-Met and PCL/PVA-Met/PCL scaffolds showed the highest correlation coefficients (R 2 ) values for the first-order release model at 0.8735 and 0.889, respectively. Since the layered structures in the literature are mainly obtained with the electrospun fiber structures, these biocompatible sandwich scaffolds, produced for the first time with 3D-printing technology, may offer an alternative to existing drug delivery systems and may be a promising candidate for enhancing diabetic wound healing.

Multiple prevalent diseases, such as osteoarthritis (OA), for which there is no cure or full understanding, affect the osteochondral unit; a complex interface tissue whose architecture, mechanical nature and physiological characteristics are still yet to be successfully reproduced in vitro. Although there have been multiple tissue engineering-based approaches to recapitulate the three dimensional (3D) structural complexity of the osteochondral unit, there are various aspects that still need to be improved. This review presents the different pre-requisites necessary to develop a human osteochondral unit construct and focuses on 3D bioprinting as a promising manufacturing technique. Examples of 3D bioprinted osteochondral tissues are reviewed, focusing on the most used bioinks, chosen cell types and growth factors. Further information regarding the applications of these 3D bioprinted tissues in the fields of disease modelling, drug testing and implantation is presented. Finally, special attention is given to the limitations that currently hold back these 3D bioprinted tissues from being used as models to investigate diseases such as OA. Information regarding improvements needed in bioink development, bioreactor use, vascularisation and inclusion of additional tissues to further complete an OA disease model, are presented. Overall, this review gives an overview of the evolution in 3D bioprinting of the osteochondral unit and its applications, as well as further illustrating limitations and improvements that could be performed explicitly for disease modelling., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

We present a digital workflow for the production of custom facial orthosis used for burn scar management using smartphone three-dimensional (3D) scanner and desktop 3D printing. 3D facial scan of a 48-year-old lady with facial burn scars was obtained. 3D modeling with open-source programs were used to create facemask then 3D printed using rigid polylactic acid (PLA) filament and semi-rigid thermoplastic polyurethane (TPU). Conventional facemask was used as a control. Each mask was worn for 7 days. Primary outcomes were level of comfort, and adherence to treatment. The conventional facemask was the most convenient followed by the TPU-facemask (mean comfort score of 9/10 and 8.7/10, respectively). Patient's compliance was high for both TPU and conventional masks, each was worn for at least 21 hours/day for 7 days. On the contrary, PLA-facemask was not well tolerated. The proposed digital workflow is simple, patient-friendly and can be adopted for resource-intensive healthcare., (© 2022. The Author(s).)

Study Design: Systematic review and meta-analysis., Objective: Various methods of pedicle screw (PS) placement in spinal fusion surgery existed, which can be grouped into conventional freehand (FH), modified freehand (MF), and image-guided methods (including fluoroscopy-based navigation (FL), computed tomography-based navigation (CT-nav), robot-assisted (RA), and ultrasound-guided (UG)). However, the literature showed mixed findings regarding their accuracy and complications. This review aimed to discover which method of PS placement has the highest accuracy and lowest complication rate in pediatric and adolescent spinal fusion surgery., Methods: A comprehensive search in MEDLINE (PubMed), EMBASE (OVID), CENTRAL, and Web of Science was conducted until May 2020 by 2 independent reviewers, followed by bias assessment with ROB 2 and ROBINS-I tools and quantification with meta-analysis. Overall evidence quality was determined with GRADE tool., Results: Four RCTs and 2 quasi-RCTs/CCTs comprising 3,830 PS placed in 291 patients (4-22 years old) were analyzed. The lowest accuracy was found in FH (78.35%) while the highest accuracy was found in MF (95.86%). MF was more accurate than FH (OR 3.34 (95% CI, 2.33-4.79), P < .00 001, I 2 = 0%). Three-dimensional printed drill template (as part of MF) was more accurate than FH (OR 3.10 (95% CI, 1.98-4.86), P < .00 001, I 2 = 14%). Overall, complications occurred in 5.84% of the patients with 0.34% revision rate. Complication events in MF was lower compared to FH (OR 0.47 (95% CI, 0.10-2.15), P = .33, I 2 = 0%)., Conclusions: Meta-analysis shows that MF is more accurate than FH in pediatric and adolescent requiring PS placement for spinal fusion surgery.

Reconstruction of peripheral nerve injuries (PNIs) with substance loss remains challenging because of limited treatment solutions and unsatisfactory patient outcomes. Currently, nerve autografting is the first-line management choice for bridging critical-sized nerve defects. The procedure, however, is often complicated by donor site morbidity and paucity of nerve tissue, raising a quest for better alternatives. The application of other treatment surrogates, such as nerve guides, remains questionable, and it is inefficient in irreducible nerve gaps. More importantly, these strategies lack customization for personalized patient therapy, which is a significant drawback of these nerve repair options. This negatively impacts the fascicle-to-fascicle regeneration process, critical to restoring the physiological axonal pathway of the disrupted nerve. Recently, the use of additive manufacturing (AM) technologies has offered major advancements to the bioengineering solutions for PNI therapy. These techniques aim at reinstating the native nerve fascicle pathway using biomimetic approaches, thereby augmenting end-organ innervation. AM-based approaches, such as three-dimensional (3D) bioprinting, are capable of biofabricating 3D-engineered nerve graft scaffolds in a patient-specific manner with high precision. Moreover, realistic in vitro models of peripheral nerve tissues that represent the physiologically and functionally relevant environment of human organs could also be developed. However, the technology is still nascent and faces major translational hurdles. In this review, we spotlighted the clinical burden of PNIs and most up-to-date treatment to address nerve gaps. Next, a summarized illustration of the nerve ultrastructure that guides research solutions is discussed. This is followed by a contrast of the existing bioengineering strategies used to repair peripheral nerve discontinuities. In addition, we elaborated on the most recent advances in 3D printing and biofabrication applications in peripheral nerve modeling and engineering. Finally, the major challenges that limit the evolution of the field along with their possible solutions are also critically analyzed. Impact statement Complex nerve injuries, including critical-sized gaps (>3 cm loss of substance), gaps involving nerve bifurcations, and those associated with ischemic environments, are difficult to manage. A biomimetic, personalized peripheral nerve tissue surrogate to address these injuries is lacking. The peripheral nerve repair market currently represents a multi-billion-dollar industry that is projected to expand. Given the clinical and economical dilemmas posed by this medical condition, it is crucial to devise novel and effective nerve substitutes. In this review article, we discuss progress in three-dimensional printing technologies, including biofabrication and nerve computer-aided design modeling, toward achieving a patient-specific and biomimetic nerve repair solution.

Severe trauma, failure of prior surgical repair, delayed presentation and excessive scarring around the flexor tendon bed often necessitate a two-stage surgical reconstruction, where a silicone spacer is used in the first stage to recreate the fibro-osseous tunnel through which the tendon graft can glide in the second stage. This staged procedure involves great commitment on the part of both patient and surgeon, over the course of several months, involving a prolonged period of rehabilitation that can be quite disruptive to the patient's life and work. Reducing this from a two-stage into a single-stage procedure, therefore, has the potential to reduce rehabilitation time and cost, expedite return to work, and improve outcomes. To address this, we developed polyurethane (PU) nanocomposite, as an engineered tendon sheath, for treatment of delayed flexor tendon division as a single-stage procedure. The clinically conformant tubular grafts were tested for their efficacy in the peroneus tertius tendon of 6 Mule sheep for 3 months. Semi-quantitative histological assessment was carried out by analysing four descriptive layers: tendon, tendon/polymer sheath interface, polymer sheath, and polymer sheath/surrounding tissue. Four (out of 6) of the implanted PU nanocomposites showed moderate to substantial healing of the injured tendons, with minimal adhesion after repair, ensuring good gliding movement. No statistical differences were observed in tendon repair based on intra-regional variation in the explanted grafts, indicating homogeneity in tendon repair. Overall, the PU nanocomposite bears morphological stability and functionality for tendon repair, in single-stage surgical reconstruction, demonstrating promising evidence for clinical translation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: The effect of bone marrow mesenchymal stromal cells (BMSCs) and platelet-rich plasma (PRP) on tendon allograft maturation in a large animal anterior cruciate ligament (ACL) reconstruction model was reported for the first time. It was hypothesised that compared with non-augmented ACL reconstruction, BMSCs and PRP would enhance graft maturation after 12 weeks and this would be detected using magnetic resonance imaging (MRI)., Methods: Fifteen sheep underwent unilateral tendon allograft ACL reconstruction using aperture fixation and were randomised into three groups (n = 5). Group 1 received 10 million allogeneic BMSCs in 2 ml fibrin sealant; Group 2 received 12 ml PRP in a plasma clot injected into the graft and bone tunnels; and Group 3 (control) received no adjunctive treatment. At autopsy at 12 weeks, a graft maturation score was determined by the sum for graft integrity, synovial coverage and vascularisation, graft thickness and apparent tension, and synovial sealing at tunnel apertures. MRI analysis (n = 2 animals per group) of the signal-noise quotient (SNQ) and fibrous interzone (FIZ) was used to evaluate intra-articular graft maturation and tendon-bone healing, respectively. Spearman's rank correlation coefficient (r) of SNQ, autopsy graft maturation score and bone tunnel diameter were analysed., Results: The BMSC group (p = 0.01) and PRP group (p = 0.03) had a significantly higher graft maturation score compared with the control group. The BMSC group scored significantly higher for synovial sealing at tunnel apertures (p = 0.03) compared with the control group. The graft maturation score at autopsy significantly correlated with the SNQ (r = - 0.83, p < 0.01). The tunnel diameter of the femoral tunnel at the aperture (r = 0.883, p = 0.03) and mid-portion (r = 0.941, p = 0.02) positively correlated with the SNQ., Conclusions: BMSCs and PRP significantly enhanced graft maturation, which indicates that orthobiologics can accelerate the biologic events in tendon allograft incorporation. Femoral tunnel expansion significantly correlated with inferior maturation of the intra-articular graft. The clinical relevance of this study is that BMSCs and PRP enhance allograft healing in a translational model, and biological modulation of graft healing can be evaluated non-invasively using MRI., (© 2020. The Author(s).)

Background: The effect of demineralized bone matrix (DBM), bone marrow-derived mesenchymal stromal cells (BMSCs), and platelet-rich plasma (PRP) on bone tunnel healing in anterior cruciate ligament reconstruction (ACLR) has not been comparatively assessed., Hypothesis: These orthobiologics would reduce tunnel widening, and the effects on tunnel diameter would be correlated with tunnel wall sclerosis., Study Design: Controlled laboratory study., Methods: A total of 20 sheep underwent unilateral ACLR using tendon allograft and outside-in interference screw fixation. The animals were randomized into 4 groups (n = 5 per group): Group 1 received 4mL of DBM paste, group 2 received 10 million BMSCs in fibrin sealant, group 3 received 12 mL of activated leukocyte-poor platelet-rich plasma, and group 4 (control) received no treatment. The sheep were euthanized after 12 weeks, and micro-computed tomography scans were performed. The femoral and tibial tunnels were divided into thirds (aperture, midportion, and exit), and the trabecular bone structure, bone mineral density (BMD), and tunnel diameter were measured. Tunnel sclerosis was defined by a higher bone volume in a 250-µm volume of interest compared with a 4-mm volume of interest surrounding the tunnel., Results: Compared with the controls, the DBM group had a significantly higher bone volume fraction (bone volume/total volume [BV/TV]) (52.7% vs 31.8%; P = .020) and BMD (0.55 vs 0.47 g/cm 3 ; P = .008) at the femoral aperture and significantly higher BV/TV at femoral midportion (44.2% vs 32.9%; P = .038). There were no significant differences between the PRP and BMSC groups versus controls in terms of trabecular bone analysis or BMD. In the controls, widening at the femoral tunnel aperture was significantly greater than at the midportion (46.7 vs 41.7 mm 2 ; P = .034). Sclerosis of the tunnel was common and most often seen at the femoral aperture. In the midportion of the femoral tunnel, BV/TV ( r = 0.52; P = .019) and trabecular number ( r S = 0.50; P = .024) were positively correlated with tunnel widening., Conclusion: Only DBM led to a significant increase in bone volume, which was seen in the femoral tunnel aperture and midportion. No treatment significantly reduced bone tunnel widening. Tunnel sclerosis in the femoral tunnel midportion was correlated significantly with tunnel widening., Clinical Relevance: DBM might have potential clinical use to enhance healing in the femoral tunnel after ACLR., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: The PRP aspects of the study were funded by a research donation from the Biotechnology Institute and Sovereign Medical Ltd, received by A.T.H., N.H., and G.B. A.T.H. received funding from a Royal Free Charity Project Grant. S.R. has received research support from OREF, Toulmin Foundation, and Angiocrine Biosciences; consulting fees from Advance Medical and Flexion Therapeutic; nonconsulting fees from Smith & Nephew; honoraria from Fidia Pharma; and royalties from Zimmer Biomet; has stock/stock options in Ortho RTI; and is a paid associate editor for The American Journal of Sports Medicine. F.H. has received royalties and consulting/speaking fees from Smith & Nephew, Stryker, MatOrtho, and Corin. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Tissue engineering is an evolving multi-disciplinary field with cutting-edge technologies and innovative scientific perceptions that promise functional regeneration of damaged tissues/organs. Tissue engineered medical products (TEMPs) are biomaterial-cell products or a cell-drug combination which is injected, implanted or topically applied in the course of a therapeutic or diagnostic procedure. Current tissue engineering strategies aim at 3D printing/bioprinting that uses cells and polymers to construct living tissues/organs in a layer-by-layer fashion with high 3D precision. However, unlike conventional drugs or therapeutics, TEMPs and 3D bioprinted tissues are novel therapeutics and need different regulatory protocols for clinical trials and commercialization processes. Therefore, it is essential to understand the complexity of raw materials, cellular components, and manufacturing procedures to establish standards that can help to translate these products from bench to bedside. These complexities are reflected in the regulations and standards that are globally in practice to prevent any compromise or undue risks to patients. This review comprehensively describes the current legislations, standards for TEMPs with a special emphasis on 3D bioprinted tissues. Based on these overviews, challenges in the clinical translation of TEMPs & 3D bioprinted tissues/organs along with their ethical concerns and future perspectives are discussed., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Several attempts have been made to develop a tool capable of evaluating breast shape and volume to aid surgical planning and outcome assessment. More recently, newer technologies such as three-dimensional (3D) scanning and 3D printing have been applied in breast assessment. The aim of this study was to review the literature to assess the applicability of 3D scanning and 3D printing in breast surgery., Methods: A literature search was carried on PubMed, Google Scholar and OVID from January 2000 to December 2019 using the keywords '3D', 'Three-dimensional', 'Three/four dimensions' and 'Breast'., Results: A total of 6564 articles were identified initially; the abstracts of 1846 articles were scanned, and 81 articles met the inclusion criteria and were included in this review. Articles were reviewed and classified according to their aims, study subjects, the software and hardware used, main outcomes and major limitations., Conclusions: These technologies are fast and easy to use, however, high costs, long processing times and the need for training might limit their application. To incorporate these technologies into standard healthcare, their efficacy and effectiveness must be demonstrated through multiple and rigorous clinical trials., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

This study investigates the usage of electrohydrodynamic (EHD)-3D printing for the fabrication of bacterial cellulose (BC)/polycaprolactone (PCL) patches loaded with different antibiotics (amoxicillin (AMX), ampicillin (AMP), and kanamycin (KAN)) for transdermal delivery. The composite patches demonstrated facilitated drug loading and encapsulation efficiency of drugs along with extended drug release profiles. Release curves were also subjected to model fitting, and it was found that drug release was optimally adapted to the Higuchi square root model for each drug. They performed a time-dependent and diffusion-controlled release from the patches and followed Fick's diffusion law by the Korsmeyer-Peppas energy law equation. Moreover, produced patches demonstrated excellent antimicrobial activity against Gram-positive ( Staphylococcus aureus ) and Gram-negative ( Escherichia coli ) strains, so they could be helpful in the treatment of chronic infectious lesions during wound closures. As different tests have confirmed, various types of antibiotics could be loaded and successfully released regardless of their types from produced BC/PCL patches. This study could breathe life into the production of antibiotic patches for local transdermal applications in wound dressing studies and improve the quality of life of patients.

In recent years, scaffolds produced in 3D printing technology have become more widespread tool due to providing more advantages than traditional methods in tissue engineering applications. In this research, it was aimed to produce patches for the treatment of tympanic membrane perforations which caused significant hearing loss by using 3D printing method. Polylactic acid(PLA) scaffolds with Chitosan(CS) and Sodium Alginate(SA) added in various ratios were prepared for artificial eardrum patches. Different amounts of chitosan and sodium alginate added to PLA increased the biocompatibility of the produced scaffolds. The created patches were designed by mimicking the thickness of the natural tympanic membrane thanks to the precision provided by the 3D printed method. The produced scaffolds were analyzed separately for chemical, morphological, mechanical and biocompatibility properties. Scanning electron microscope (SEM), Fourier-transform infrared (FT-IR) spectroscopy was performed to observe the surface morphology and chemical structure of the scaffolds. Mechanical, thermal and physical properties, swelling and degradation behaviors were examined to fully analyze whole characteristic features of the samples. Cell culture study was also performed to demonstrate the biocompatibility properties of the fabricated scaffolds with human adipose tissue-derived mesenchymal stem cells (hAD-MSCs). 15 wt % PLA was selected as the control group and among all concentrations of CS and SA, groups containing 3 wt% CS and 3 wt% SA showed significantly superior and favorable features in printing quality. The research continued with these two scaffolds (3 wt% CS, and 3 wt% SA), which showed improved print quality when added to PLA. Overall, these results show that PLA/CS and PLA/SA 3D printed artificial patches have the potential to tissue engineering solutions to repair tympanic membrane perforation for people with hearing loss., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To: (1) design an artifact-free 3D-printed MR-safe temporary transfer device, (2) engineer bone-pins from carbon fiber reinforced polyether ether ketone (CFR-PEEK), (3) evaluate the imaging artifacts of CFR-PEEK, and (4) confirm the osteointegration potential of CFR-PEEK, thus enhancing 3D-planning of bony advancements in hemifacial microsomia using sequential magnetic resonance imaging (MRI)., Study Design: Engineered CRF-PEEK bone pins and a 3D printed ex-fix device were implanted into a sheep head and imaged with MRI and computed tomography . The osseointegration and bony compatibility potential of CFR-PEEK was assessed with scanning electron microscopy images of MC3T3 preosteoblast cells on the surface of the material., Results: The CFR-PEEK pins resulted in a signal void equivalent to the dimension of the pin, with no adjacent areas of MR-signal loss or computed tomography artifact. MCT3 cells adhered and proliferated on the surface of the discs by forming a monolayer of cells, confirming compatibility and osseointegration potential., Conclusion: A 3D printed transfer device could be utilized temporarily during MRI to permit artifact-free 3D planning. CFR-PEEK pins eliminate imaging artifact permitting sequential MRI examination. In combination, this has the potential to enhance distraction osteogenesis, by permitting accurate three-dimensional planning without ionizing radiation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Three-dimensional (3D) printing application is a promising method for bone tissue engineering. For enhanced bone tissue regeneration, it is essential to have printable composite materials with appealing properties such as construct porous, mechanical strength, thermal properties, controlled degradation rates, and the presence of bioactive materials. In this study, polycaprolactone (PCL), gelatin (GEL), bacterial cellulose (BC), and different hydroxyapatite (HA) concentrations were used to fabricate a novel PCL/GEL/BC/HA composite scaffold using 3D printing method for bone tissue engineering applications. Pore structure, mechanical, thermal, and chemical analyses were evaluated. 3D scaffolds with an ideal pore size (~300 µm) for use in bone tissue engineering were generated. The addition of both bacterial cellulose (BC) and hydroxyapatite (HA) into PCL/GEL scaffold increased cell proliferation and attachment. PCL/GEL/BC/HA composite scaffolds provide a potential for bone tissue engineering applications.

This study demonstrates the development and application of a novel workflow for designing and fabricating orthoses, using a combination of 3D scanning and 3D printing technologies. The workflow is applied to a clinically relevant translational case study in a patient with a neurological disorder and complex clinical needs. All traditional and commercial approaches to helping the patient's cervical instability and resulting 'head-drop' had previously failed, with associated progressive deterioration in the patient's clinical state and posture. The workflow was developed to design and fabricate a bespoke device for this patient with no viable alternative therapy. The workflow was developed to generate 3D printable geometry from obtained 3D scan data. The workflow includes algorithms to relax geometry, distribute material efficiently and for variational cutting of orthosis padding material. The 3D patient scan was validated against actual measurements to ensure accuracy of measurements. A total of four prototypes were produced with each iteration being improved based on patient and clinical feedback. There was a progressive improvement in subjective feedback through each iteration at sites of discomfort and overall comfort score. There was a marked improvement in the patient's posture with correction at the cervical and lumbar spine with the 3D-printed padded collar being worn for 4 hour periods. This study has implications for the rapid production of personalised orthoses which can help reduce patient waiting time, improve patient compliance, reduce pain and reduce further deterioration. The workflow could form the basis for an integrated process, whereby a single hospital visit results in a bespoke orthosis optimised and personalised for each patient.

Bone and cartilage craniofacial defects due to trauma or congenital deformities pose a difficult problem for reconstructive surgeons. Human adipose stem cells (ADSCs) can differentiate into bone and cartilage and together with suitable scaffolds could provide a promising system for skeletal tissue engineering. It has been suggested that nanomaterials can direct cell behavior depending on their surface nanotopographies. Thus, this study examined whether by altering a nanoscaffold surface using radiofrequency to excite gases, argon (Ar), nitrogen (N 2 ) and oxygen (O 2 ) with a single step technique, we could enhance the osteogenic and chondrogenic potential of ADSCs. At 24 h, Ar modification promoted the highest increase in ADSCs adhesion as indicated by upregulation of vinculin and focal adhesion kinase (FAK) expression compared to O 2 and N 2 scaffolds. Furthermore, ADSCs on Ar-modified nanocomposite polymer POSS-PCU scaffolds upregulated expression of bone markers, alkaline phosphatase, collagen I and osteocalcin after 3 weeks. Cartilage markers, aggrecan and collagen II, were also upregulated on Ar-modified scaffolds at the mRNA and protein level. Finally, all plasma treated scaffolds supported tissue ingrowth and angiogenesis after grafting onto the chick chorioallantoic membrane. Ar promoted greater expression of vascular endothelial growth factor and laminin in ovo compared to O 2 and N 2 scaffolds as shown by immunohistochemistry. This study provides an important understanding into which surface chemistries best support the osteogenic and chondrogenic differentiation of ADSCs that could be harnessed for regenerative skeletal applications. Argon surface modification is a simple tool that can promote ADSC skeletal differentiation that is easily amenable to translation into clinical practice., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Bone regeneration requires porous and mechanically stable scaffolds to support tissue integration and angiogenesis, which is essential for bone tissue regeneration. With the advent of additive manufacturing processes, production of complex porous architectures has become feasible. However, a balance has to be sorted between the porous architecture and mechanical stability, which facilitates bone regeneration for load bearing applications. The current study evaluates the use of high resolution digital light processing (DLP) -based additive manufacturing to produce complex but mechanical stable scaffolds based on β-tricalcium phosphate (β-TCP) for bone regeneration. Four different geometries: a rectilinear Grid, a hexagonal Kagome, a Schwarz primitive, and a hollow Schwarz architecture are designed with 400 μm pores and 75 or 50 vol% porosity. However, after initial screening for design stability and mechanical properties, only the rectilinear Grid structure, and the hexagonal Kagome structure are found to be reproducible and showed higher mechanical properties. Micro computed tomography (μ-CT) analysis shows <2 vol% error in porosity and <6% relative deviation of average pore sizes for the Grid structures. At 50 vol% porosity, this architecture also has the highest compressive strength of 44.7 MPa (Weibull modulus is 5.28), while bulk specimens reach 235 ± 37 MPa. To evaluate suitability of 3D scaffolds produced by DLP methods for bone regeneration, scaffolds were cultured with murine preosteoblastic MC3T3-E1 cells. Short term study showed cell growth over 14 d, with more than two-fold increase of alkaline phosphatase (ALP) activity compared to cells on 2D tissue culture plastic. Collagen deposition was increased by a factor of 1.5-2 when compared to the 2D controls. This confirms retention of biocompatible and osteo-inductive properties of β-TCP following the DLP process. This study has implications for designing of the high resolution porous scaffolds for bone regenerative applications and contributes to understanding of DLP based additive manufacturing process for medical applications.

Background: Synthetic implants are being used to restore injured or damaged tissues following cancer resection and congenital diseases. However, the survival of large tissue implant replacements depends on their ability to support angiogenesis that if limited, causes extrusion and infection of the implant. This study assessed the beneficial effect of platelet-rich plasma (PRP) and adipose-derived stem cells (ADSCs) on synthetic biomaterials in combination with argon plasma surface modification to enhance vascularisation of tissue-engineered constructs., Methods: Non-biodegradable polyurethane scaffolds were manufactured and modified with plasma surface modification using argon gas (PM). Donor rats were then used to extract ADSCs and PRP to modify the scaffolds further. Scaffolds with and without PM were modified with and without ADSCs and PRP and subcutaneously implanted in the dorsum of rats for 3 months. After 12 weeks, the scaffolds were excised and the degree of tissue integration using H&E staining and Masson's trichrome staining, angiogenesis by CD31 and immune response by CD45 and CD68 immunohistochemistry staining was examined., Results: H&E and Masson's trichrome staining showed PM+PRP+ADSC and PM+ADSC scaffolds had the greatest tissue integration, but there was no significant difference between the two scaffolds (p < 0.05). The greatest vessel formation after 3 months was shown with PM+PRP+ADSC and PM+ADSC scaffolds using CD31 staining compared to all other scaffolds (p < 0.05). The CD45 and CD68 staining was similar between all scaffolds after 3 months showing the ADSCs or PRP had no effect on the immune response of the scaffolds., Conclusions: Argon plasma surface modification enhanced the effect of adipose-derived stem cells effect on angiogenesis and tissue integration of polyurethane scaffolds. The combination of ADSCs and argon plasma modification may improve the survival of large tissue implants for regenerative applications.

Redox-active G-quadruplex hydrogels were prepared by dynamic boronate ester formation between ferroceneboronic acid and guanosine. Dynamic boronate esters imparted thixotropic and 3D-printability to the hydrogel. Initially, the ferrocene moiety was oxidised to produce a weaker ferrocenium-based green hydrogel. However, the less stable ferrocenium converted into more stable ferrocene to produce a hydrophobic, water-stable and robust hydrogel., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Tissue expansion reconstruction in clinical practice has existed for over half a century. The technique was initially used for breast reconstruction but later found its use in reconstruction of excisional defects resulting from a variety of causes including surgery for post-burn/post-traumatic deformities, congenital giant naevi, skin cancer, etc. It offers an improved matching of skin colour and texture, and avoids the high infrastructure requirements of microsurgery for free flap transfers. We present a systematic literature review of 35 worldwide English language articles with representative cases of paediatric tissue expansion reconstruction of burn injuries of the head and neck. The review identified 68 children of an average age of 11.3 years. The most common burn aetiology was flame burn injury. The average area to be reconstructed was of 206 cm 2 and patients went through expansion processes for an average of 99.7 days. Three articles included cases in which patients had more than one expansion session. Supportive techniques provide examples of developments in the area of tissue expansion reconstruction such as self-inflating expanders and endoscopic approaches. Further studies focussing on particular indications, age groups and anatomical locations of tissues to be expanded are required in order to improve the understanding of this technique's limitations and continue its development., (© 2018 The Author(s).)

An effective sterilisation technique that maintains structure integrity, mechanical properties, and biocompatibility is essential for the translation of new biomaterials to the clinical setting. We aimed to establish an effective sterilisation technique for a biodegradable (POSS-PCL) and nonbiodegradable (POSS-PCU) nanocomposite scaffold that maintains stem cell biocompatibility. Scaffolds were sterilised using 70% ethanol, ultraviolet radiation, bleach, antibiotic/antimycotic, ethylene oxide, gamma irradiation, argon plasma, or autoclaving. Samples were immersed in tryptone soya broth and thioglycollate medium and inspected for signs of microbial growth. Scaffold surface and mechanical and molecular weight properties were investigated. AlamarBlue viability assay of adipose derived stem cells (ADSC) seeded on scaffolds was performed to investigate metabolic activity. Confocal imaging of rhodamine phalloidin and DAPI stained ADSCs was performed to evaluate morphology. Ethylene oxide, gamma irradiation, argon plasma, autoclaving, 70% ethanol, and bleach were effective in sterilising the scaffolds. Autoclaving, gamma irradiation, and ethylene oxide led to a significant change in the molecular weight distribution of POSS-PCL and gamma irradiation and ethylene oxide to that of POSS-PCU (p<0.05). UV, ethanol, gamma irradiation, and ethylene oxide caused significant changes in the mechanical properties of POSS-PCL (p<0.05). Argon was associated with significantly higher surface wettability and ADSC metabolic activity (p<0.05). In this study, argon plasma was an effective sterilisation technique for both nonbiodegradable and biodegradable nanocomposite scaffolds. Argon plasma should be further investigated as a potential sterilisation technique for medical devices.

Lumbar fusion surgery is an established procedure for the treatment of low back pain. Despite the wide set of alternative fusion techniques and existing devices, uniform guidelines are not available yet and common surgical trends are scarcely investigated.The purpose of this UK-based study was to provide a descriptive portrait of current surgeons' practice and implant preferences in lumbar fusion surgery.A UK-based in-person survey was designed for this study and submitted to a group of consultant spinal surgeons (n = 32). Fifteeen queries were addressed based on different aspects of surgeons' practice: lumbar fusion techniques, implant preferences, and bone grafting procedures. Answers were analyzed by means of descriptive statistics.Thirty-two consultant spinal surgeons completed the survey. There was clear consistency on the relevance of a patient-centered management (82.3%), along with a considerable variability of practice on the preferred fusion approach. Fixation surgery was found to be largely adopted (96.0%) and favored over stand-alone cages. With regards to the materials, titanium cages were the most used (54.3%). The geometry of the implants influenced the choice of lumbar cages (81.3%). Specifically, parallel-shape cages were mostly avoided (89.2%) and hyperlordotic cages were preferred at the lower lumbar levels. However, there was no design for lumbar cages which was consistently favored. Autograft bone graft surgeries were the most common (60.0%). Amongst the synthetic options, hydroxyapatite-based bone graft substitutes (76.7%) in injectable paste form (80.8%) were preferred.Current lumbar fusion practice is variable and patient-oriented. Findings from this study highlight the need for large-scale investigative surveys and clinical studies aimed to set specific guidelines for certain pathologies or patient categories.

Extrudable G-quadruplex hydrogels were prepared at physiological pH. Gels with suitable mechanical properties were explored as 3D-bioinks. The 3D printing process is driven by injectability and the highly thixotropic and self-healable nature of the gel. High cell viability and homogeneous cell distribution within the gel make it a promising material as a 3D bioink.

In the current study, we present the synthesis of novel low cost bio-polyurethane compositions with variable mechanical properties based on castor oil and glycerol for biomedical applications. A detailed investigation of the physicochemical properties of the polymer was carried out by using mechanical testing, ATR-FTIR, and X-ray photoelectron spectroscopy (XPS). Polymers were also tested in short term in-vitro cell culture with human mesenchymal stem cells to evaluate their biocompatibility for potential applications as biomaterial. FTIR analysis confirmed the synthesis of castor oil and glycerol based PU polymers. FTIR also showed that the addition of glycerol as co-polyol increases crosslinking within the polymer backbone hence enhancing the bulk mechanical properties of the polymer. XPS data showed that glycerol incorporation leads to an enrichment of oxidized organic species on the surface of the polymers. Preliminary investigation into in vitro biocompatibility showed that serum protein adsorption can be controlled by varying the glycerol content with polymer backbone. An alamar blue assay looking at the metabolic activity of the cells indicated that castor oil based PU and its variants containing glycerol are non-toxic to the cells. This study opens an avenue for using low cost bio-polyurethane based on castor oil and glycerol for biomedical applications., (© 2017 The Authors Biopolymers Published by Wiley Periodicals, Inc.)

The latest and fastest-growing innovation in the medical field has been the advent of three-dimensional printing technologies, which have recently seen applications in the production of low-cost, patient-specific medical implants. While a wide range of three-dimensional printing systems has been explored in manufacturing anatomical models and devices for the medical setting, their applications are cutting-edge in the field of spinal surgery. This review aims to provide a comprehensive overview and classification of the current applications of three-dimensional printing technologies in spine care. Although three-dimensional printing technology has been widely used for the construction of patient-specific anatomical models of the spine and intraoperative guide templates to provide personalized surgical planning and increase pedicle screw placement accuracy, only few studies have been focused on the manufacturing of spinal implants. Therefore, three-dimensional printed custom-designed intervertebral fusion devices, artificial vertebral bodies and disc substitutes for total disc replacement, along with tissue engineering strategies focused on scaffold constructs for bone and cartilage regeneration, represent a set of promising applications towards the trend of individualized patient care.

This study presents a simple and reproducible method of micropatterning the novel nanocomposite polymer (POSS-PCU) using a sacrificial phosphate glass fiber template for tendon tissue engineering applications. The diameters of the patterned scaffolds produced were dependent on the diameter of the glass fibers (15 μm) used. Scaffolds were tested for their physical properties and reproducibility using various microscopy techniques. For the first time, we show that POSS-PCU supports growth of human tenocytes cells. Furthermore, we show that cellular alignment, their biological function and expression of various tendon related proteins such as scleraxis, collagen I and III, tenascin-C are significantly elevated on the micropatterned polymer surfaces compared to flat samples. This study demonstrated a simple, reproducible method of micropatterning POSS-PCU nanocomposite polymer for novel tendon repair applications, which when provided with physical cues could help mimic the microenvironment of tenocytes cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Human adipose derived stem cells (ADSCs) are being explored for the repair of craniofacial defects due to their multi-differentiation potential and ease of isolation and expansion. Crucial to using ADSCs for craniofacial repair is the availability of materials with appropriate biomechanical properties that can support their differentiation into bone and cartilage. We tested the hypothesis that different modifications of chemical groups on the surface of a nanocomposite polymer could increase human ADSC adhesion and selectively enhance their osteogenic and chondrogenic differentiation. We show that the COOH modification significantly promoted initial cell adhesion and proliferation over 14days compared to NH 2 surfaces. Expression of focal adhesion kinase and vinculin was enhanced after plasma surface polymerisation at 24h. The COOH modification significantly enhanced chondrogenic differentiation as indicated by up-regulation of aggrecan and collagen II transcripts. In contrast, NH 2 group functionalised scaffolds promoted osteogenic differentiation with significantly enhanced expression of collagen I, alkaline phosphatase and osteocalcin both at the gene and protein level. Finally, chorioallantoic membrane grafting demonstrated that both NH 2 and COOH functionalised scaffolds seeded with ADSCs were biocompatible and supported vessel ingrowth apparently to a greater degree than unmodified scaffolds. In summary, our study shows the ability to direct ADSC chondrogenic and osteogenic differentiation by deposition of different chemical groups through plasma surface polymerisation. Hence this approach could be used to selectively enhance bone or cartilage formation before implantation in vivo to repair skeletal defects., Statement of Significance: Human adipose derived stem cells (hADSCs) are an exciting stem cell source for regenerative medicine due to their plentiful supply and ease of isolation. However, the optimal environmental cues to direct stem cells towards certain lineages change have to has not been identified. We have shown that by modifying the surface of the scaffold with specific chemical groups using plasma surface polymerisation techniques we can control ADSCs differentiation. This study shows that ADSCs can be differentiated towards osteogenic and chondrogenic lineages on amine (NH 2 ) and carboxyl (COOH) modified scaffolds respectively. Plasma polymerisation can be easily applied to other biomaterial surfaces to direct stem cell differentiation for the regeneration of bone and cartilage., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

We demonstrate an efficient method to produce mechano-responsive polymeric scaffolds which can alter cellular functions using two different functionalized (OH and NH2) silica nano-fillers. Fumed silica-hydroxyl and fumed silica-amine nano-fillers were mixed with a biocompatible polymer (POSS-PCU) at various wt% to produce scaffolds. XPS and mechanical testing demonstrate that bulk mechanical properties are modified without changing the scaffold's surface chemistry. Mechanical testing showed significant change in bulk properties of POSS-PCU scaffolds with an addition of silica nanofillers as low as 1% (P<0.01). Scaffolds modified with NH2 silica showed significantly higher bulk mechanical properties compared to the one modified with the OH group. Enhanced cell adhesion, proliferation and collagen production over 14days were observed on scaffolds with higher bulk mechanical properties (NH2) compared to those with lower ones (unmodified and OH modified) (P<0.05) during in vitro analysis. This study provides an effective method of manufacturing mechano-responsive polymeric scaffolds, which can help to customize cellular responses for biomaterial applications., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

This study present amino functionalization of biocompatible polymer polyhedral oligomeric silsequioxane-poly(carbonate-urea) urethane (POSS-PCU) using plasma polymerization process to induce osteogenic differentiation of adipose derived stem cells (ADSCs). Optimization of plasma polymerization process was carried out keeping cell culture application in mind. Thus, samples were rigorously tested for retention of amino groups under both dry and wet conditions. Physio-chemical characterization was carried out using ninhydrin test, X-ray photon spectroscopy, scanning electron microscopy, and static water contact analysis. Results from physio chemical characterization shows that functionalization of the amino group is not stable under wet conditions and optimization of plasma process is required for stable bonding of amino groups to the POSS-PCU polymer. Optimized samples were later tested in vitro in short and long-term culture to study differentiation of ADSCs on amino modified samples. Short-term cell culture shows that initial cell attachment was significantly (p < 0.001) improved on amine modified samples (NH2-POSS-PCU) compared to unmodified POSS-PCU. NH2-POSS-PCU samples also facilitates osteogenic differentiation of ADSCs as confirmed by immunological staining of cells for extracellular markers such as collagen Type I and osteopontin. Quantification of total collagen and ALP activity also shows significant (p < 0.001) increase on NH2-POSS-PCU samples compared to unmodified POSS-PCU. A pilot study also confirms that these optimized amino modified POSS-PCU samples can further be functionalized using bone inducing peptide such as KRSR using conventional wet chemistry. This further provides an opportunity for biofunctionalization of the polymer for various tissue specific applications.

Spinal fusion is the gold standard surgical procedure for degenerative spinal conditions when conservative therapies have been unsuccessful in rehabilitation of patients. Novel strategies are required to improve biocompatibility and osseointegration of traditionally used materials for lumbar cages. Furthermore, new design and technologies are needed to bridge the gap due to the shortage of optimal implant sizes to fill the intervertebral disc defect. Within this context, additive manufacturing technology presents an excellent opportunity to fabricate ergonomic shape medical implants. The goal of this study is to design and manufacture a 3D-printed lumbar cage for lumbar interbody fusion. Optimisations of the proposed implant design and its printing parameters were achieved via in silico analysis. The final construct was characterised via scanning electron microscopy, contact angle, x-ray micro computed tomography (μCT), atomic force microscopy, and compressive test. Preliminary in vitro cell culture tests such as morphological assessment and metabolic activities were performed to access biocompatibility of 3D-printed constructs. Results of in silico analysis provided a useful platform to test preliminary cage design and to find an optimal value of filling density for 3D printing process. Surface characterisation confirmed a uniform coating of nHAp with nanoscale topography. Mechanical evaluation showed mechanical properties of final cage design similar to that of trabecular bone. Preliminary cell culture results showed promising results in terms of cell growth and activity confirming biocompatibility of constructs. Thus for the first time, design optimisation based on computational and experimental analysis combined with the 3D-printing technique for intervertebral fusion cage has been reported in a single study. 3D-printing is a promising technique for medical applications and this study paves the way for future development of customised implants in spinal surgical applications.

Current surgical reconstruction of facial defects including nose or ear involves harvesting patient's own autologous tissue, causing donor site morbidity and is limited by tissue availability. The use of alternative synthetic materials is also limited due to complications related to poor tissue integration and angiogenesis, which lead to extrusion of implants and infection. We intend to meet this clinical challenge by using a novel nanocomposite called polyhedral oligomeric silsesquioxane poly(carbonate-urea)urethane (POSS-PCU), which has already been successfully taken to the clinical bench-side as a replacement for trachea, tear duct and vascular by-pass graft. In this study, we aimed to enhance tissue integration and angiogenesis of POSS-PCU using an established surface treatment technique, plasma surface polymerisation (PSP), functionalising the surface using NH2 and COOH chemical groups. Physical characterisation of scaffolds was achieved by using a number of techniques, including water contact angle, SEM, AFM and XPS to study the effects of PSM modification on the POSS-PCU nanocomposite in detail, which has not been previously documented. Wettability evaluation confirmed that scaffolds become hydrophilic and AFM analysis confirmed that nano topographical alterations resulted as a consequence of PSP treatment. Chemical functionalisation was confirmed using XPS, which suggested the presence of NH2 and COOH functional groups on the scaffolds. The modified scaffolds were then tested both in vitro and in vivo to investigate the potential of PSP modified POSS-PCU scaffolds on tissue integration and angiogenesis. In vitro analysis confirmed that PSM modification resulted in higher cellular growth, proliferation and ECM production as assessed by biochemical assays and immunofluorescence. Subcutaneous implantation of modified POSS-PCU scaffolds was then carried out over 12-weeks, resulting in enhanced tissue integration and angiogenesis (p < 0.05). This study demonstrates a simple and cost effective surface modification method to overcome the current challenge of implant extrusion and infection caused by poor integration and angiogenesis.