Regenerative Medicine Approaches Research Articles

Cytochalasin B Influences Cytoskeletal Organization and Osteogenic Potential of Human Wharton's Jelly Mesenchymal Stem Cells.

Among perinatal stem cells of the umbilical cord, human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) are of great interest for cell-based therapy approaches in regenerative medicine, showing some advantages over other MSCs. In fact, hWJ-MSCs, placed between embryonic and adult MSCs, are not tumorigenic and are harvested with few ethical concerns. Furthermore, these cells can be easily cultured in vitro, maintaining both stem properties and a high proliferative rate for several passages, as well as trilineage capacity of differentiation. Recently, it has been demonstrated that cytoskeletal organization influences stem cell biology. Among molecules able to modulate its dynamics, Cytochalasin B (CB), a cyto-permeable mycotoxin, influences actin microfilament polymerization, thus affecting several cell properties, such as the ability of MSCs to differentiate towards a specific commitment. Here, we investigated for the first time the effects of a 24 h-treatment with CB at different concentrations (0.1-3 μM) on hWJ-MSCs. CB influenced the cytoskeletal organization in a dose-dependent manner, inducing changes in cell number, proliferation, shape, and nanomechanical properties, thus promoting the osteogenic commitment of hWJ-MSCs, as confirmed by the expression analysis of osteogenic/autophagy markers.

Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective.

Rejection of solid organ transplant and graft versus host disease (GvHD) continue to be challenging in post transplantation management. The introduction of calcineurin inhibitors dramatically improved recipients' short-term prognosis. However, long-term clinical outlook remains poor, moreover, the lifelong dependency on these toxic drugs leads to chronic deterioration of graft function, in particular the renal function, infections and de-novo malignancies. These observations led investigators to identify alternative therapeutic options to promote long-term graft survival, which could be used concomitantly, but preferably, replace pharmacologic immunosuppression as standard of care. Adoptive T cell (ATC) therapy has evolved as one of the most promising approaches in regenerative medicine in the recent years. A range of cell types with disparate immunoregulatory and regenerative properties are actively being investigated as potential therapeutic agents for specific transplant rejection, autoimmunity or injury-related indications. A significant body of data from preclinical models pointed to efficacy of cellular therapies. Significantly, early clinical trial observations have confirmed safety and tolerability, and yielded promising data in support of efficacy of the cellular therapeutics. The first class of these therapeutic agents commonly referred to as advanced therapy medicinal products have been approved and are now available for clinical use. Specifically, clinical trials have supported the utility of CD4+CD25+FOXP3+ regulatory T cells (Tregs) to minimize unwanted or overshooting immune responses and reduce the level of pharmacological immunosuppression in transplant recipients. Tregs are recognized as the principal orchestrators of maintaining peripheral tolerance, thereby blocking excessive immune responses and prevent autoimmunity. Here, we summarize rationale for the adoptive Treg therapy, challenges in manufacturing and clinical experiences with this novel living drug and outline future perspectives of its use in transplantation.

Optics-Free, In Situ Swelling Monitoring of Articular Cartilage with Graphene Strain Sensors.

Articular cartilage derives its load-bearing strength from the mechanical and physiochemical coupling between the collagen network and negatively charged proteoglycans, respectively. Current disease modeling approaches and treatment strategies primarily focus on cartilage stiffness, partly because indentation tests are readily accessible. However, stiffness measurements via indentation alone cannot discriminate between proteoglycan degradation versus collagen degradation, and there is a lack of methods to monitor physiochemical contributors in full-stack tissue. To decouple these contributions, here, we developed a platform that measures tissue swelling in full-depth equine cartilage explants using piezoresistive graphene strain sensors. These piezoresistive strain sensors are embedded within an elastomer bulk and have sufficient sensitivity to resolve minute, real-time changes in swelling. By relying on simple DC resistance measurements over optical techniques, our platform can analyze multiple samples in parallel. Using these devices, we found that cartilage explants under enzymatic digestion showed distinctive swelling responses to a hypotonic challenge and established average equilibrium swelling strains in healthy cartilage (4.6%), cartilage with proteoglycan loss (0.5%), and in cartilage with both collagen and proteoglycan loss (-2.6%). Combined with histology, we decoupled the pathologic swelling responses as originating either from reduced fixed charge density or from loss of intrinsic stiffness of the collagen matrix in the superficial zone. By providing scalable and in situ monitoring of cartilage swelling, our platform could facilitate regenerative medicine approaches aimed at restoring osmotic function in osteoarthritic cartilage or could be used to validate physiologically relevant swelling behavior in synthetic hydrogels.

Hypoxia-sensitive miRNA regulation via CRISPR/dCas9 loaded in hybrid exosomes: A novel strategy to improve embryo implantation and prevent placental insufficiency during pregnancy.

Assisted reproductive techniques as a new regenerative medicine approach have significantly contributed to solving infertility problems that affect approximately 15% of couples worldwide. However, the success rate of an in vitro fertilization (IVF) cycle remains only about 20%-30%, and 75% of these losses are due to implantation failure (the crucial rate-limiting step of gestation). Implantation failure and abnormal placenta formation are mainly caused by defective adhesion, invasion, and angiogenesis. Placental insufficiency endangers both the mother's and the fetus's health. Therefore, we suggested a novel treatment strategy to improve endometrial receptivity and implantation success rate. In this strategy, regulating mir-30d expression as an upstream transcriptomic modifier of the embryo implantation results in modified expression of the involved genes in embryonic adhesion, invasion, and angiogenesis and consequently impedes implantation failure. For this purpose, "scaffold/matrix attachment regions (S/MARs)" are employed as non-viral episomal vectors, transfecting into trophoblasts by exosome-liposome hybrid carriers. These vectors comprise CRISPR/dCas9 with a guide RNA to exclusively induce miR-30d gene expression in hypoxic stress conditions. In order to avoid concerns about the fetus's genetic manipulation, our vector would be transfected specifically into the trophoblast layer of the blastocyst via binding to trophoblast Erb-B4 receptors without entering the inner cell mass. Additionally, S/MAR episomal vectors do not integrate with the original cell DNA. As an on/off regulatory switch, a hypoxia-sensitive promoter (HRE) is localized upstream of dCas9. The miR-30d expression increases before and during the implantation and placental insufficiency conditions and is extinguished after hypoxia elimination. This hypothesis emphasizes that improving the adhesion, invasion, and angiogenesis in the uterine microenvironment during pregnancy will result in increased implantation success and reduced placental insufficiency, as a new insight in translational medicine.

Biological Scaffolds for Congenital Heart Disease.

Congenital heart disease (CHD) is the most predominant birth defect and can require several invasive surgeries throughout childhood. The absence of materials with growth and remodelling potential is a limitation of currently used prosthetics in cardiovascular surgery, as well as their susceptibility to calcification. The field of tissue engineering has emerged as a regenerative medicine approach aiming to develop durable scaffolds possessing the ability to grow and remodel upon implantation into the defective hearts of babies and children with CHD. Though tissue engineering has produced several synthetic scaffolds, most of them failed to be successfully translated in this life-endangering clinical scenario, and currently, biological scaffolds are the most extensively used. This review aims to thoroughly summarise the existing biological scaffolds for the treatment of paediatric CHD, categorised as homografts and xenografts, and present the preclinical and clinical studies. Fixation as well as techniques of decellularisation will be reported, highlighting the importance of these approaches for the successful implantation of biological scaffolds that avoid prosthetic rejection. Additionally, cardiac scaffolds for paediatric CHD can be implanted as acellular prostheses, or recellularised before implantation, and cellularisation techniques will be extensively discussed.

Bioprinting extracellular vesicles as a ‘cell-free' regenerative medicine approach

Regenerative medicine involves the restoration of tissue or organ function via the regeneration of these structures. As promising regenerative medicine approaches, either extracellular vesicles (EVs) or bioprinting are emerging stars to regenerate various tissues and organs (i.e., bone and cardiac tissues). Emerging as highly attractive cell-free, off-the-shelf nanotherapeutic agents for tissue regeneration, EVs are bilayered lipid membrane particles that are secreted by all living cells and play a critical role as cell-to-cell communicators through an exchange of EV cargos of protein, genetic materials, and other biological components. 3D bioprinting, combining 3D printing and biology, is a state-of-the-art additive manufacturing technology that uses computer-aided processes to enable simultaneous patterning of 3D cells and tissue constructs in bioinks. Although developing an effective system for targeted EVs delivery remains challenging, 3D bioprinting may offer a promising means to improve EVs delivery efficiency with controlled loading and release. The potential application of 3D bioprinted EVs to regenerate tissues has attracted attention over the past few years. As such, it is timely to explore the potential and associated challenges of utilizing 3D bioprinted EVs as a novel ‘cell-free’ alternative regenerative medicine approach. In this review, we describe the biogenesis and composition of EVs, and the challenge of isolating and characterizing small EVs - sEVs (< 200 nm). Common 3D bioprinting techniques are outlined and the issue of bioink printability is explored. After applying the following search strategy in PubMed: ‘bioprinted exosomes’ or ‘3D bioprinted extracellular vesicles’, eight studies utilizing bioprinted EVs were found that have been included in this scoping review. Current studies utilizing bioprinted sEVs for various in vitro and in vivo tissue regeneration applications, including angiogenesis, osteogenesis, immunomodulation, chondrogenesis and myogenesis, are discussed. Finally, we explore the current challenges and provide an outlook on possible refinements for bioprinted sEVs applications.

High-Speed-Microscopy for Scalable Quality Control in Automated Production of Stem Cell Spheroids for Tissue Engineering

The EU Horizon 2020 project »JointPromise« implies the conception and implementation of an end-to-end automated production platform for three-dimensional joint implants, paving the way for tissue-engineered implants able to regenerate deep osteochondral defects. Spheroid-based implants provide a novel approach in tissue engineering by aggregating progenitor cells into potent microtissues. After the differentiation of cartilaginous microtissues, functional joint implants are assembled via 3D bioprinting to match the complex structural organization of native cartilage tissue. As the automation approach of the project aims to overcome bottlenecks in manual production such as product variability, lack of scalability and high personnel costs, a high-throughput quality control system is crucial for the production of reliable Advanced Therapy Medicinal Products (ATMPs).By establishing not only a technical solution for the full digitization of the cell culture plates but also an intelligent image processing algorithm for the detection of the cell spheroids, relevant process parameters like size distribution and growth curves can be detected. Critical thresholds in spheroid growth are evaluated to minimize risks of carcinogenic tissue formation in vivo as well as to define harvest criteria to prevent inhomogeneous bioprinting results. In order to calculate the required throughput and elaborate optimization potentials of the automated spheroid production, voids in the cultivation vessel or disrupted aggregates due to media changes or transportation are detected. Ultimately, the highspeed-microscopy complies with the requirements of a high-throughput automated cell production platform to meet the rising demand for alternative therapeutic approaches in regenerative medicine.

Renal tissue engineering for regenerative medicine using polymers and hydrogels.

Chronic Kidney Disease (CKD) is a growing worldwide problem, leading to end-stage renal disease (ESRD). Current treatments for ESRD include haemodialysis and kidney transplantation, but both are deemed inadequate since haemodialysis does not address all other kidney functions, and there is a shortage of suitable donor organs for transplantation. Research in kidney tissue engineering has been initiated to take a regenerative medicine approach as a potential treatment alternative, either to develop effective cell therapy for reconstruction or engineer a functioning bioartificial kidney. Currently, renal tissue engineering encompasses various materials, mainly polymers and hydrogels, which have been chosen to recreate the sophisticated kidney architecture. It is essential to address the chemical and mechanical aspects of the materials to ensure they can support cell development to restore functionality and feasibility. This paper reviews the types of polymers and hydrogels that have been used in kidney tissue engineering applications, both natural and synthetic, focusing on the processing and formulation used in creating bioactive substrates and how these biomaterials affect the cell biology of the kidney cells used.

Unveiling the potential of melt electrowriting in regenerative dental medicine.

For nearly three decades, tissue engineering strategies have been leveraged to devise effective therapeutics for dental, oral, and craniofacial (DOC) regenerative medicine and treat permanent deformities caused by many debilitating health conditions. In this regard, additive manufacturing (AM) allows the fabrication of personalized scaffolds that have the potential to recapitulate native tissue morphology and biomechanics through the utilization of several 3D printing techniques. Among these, melt electrowriting (MEW) is a versatile direct electrowriting process that permits the development of well-organized fibrous constructs with fiber resolutions ranging from micron to nanoscale. Indeed, MEW offers great prospects for the fabrication of scaffolds mimicking tissue specificity, healthy and pathophysiological microenvironments, personalized multi-scale transitions, and functional interfaces for tissue regeneration in medicine and dentistry. Excitingly, recent work has demonstrated the potential of converging MEW with other AM technologies and/or cell-laden scaffold fabrication (bioprinting) as a favorable route to overcome some of the limitations of MEW for DOC tissue regeneration. In particular, such convergency fabrication strategy has opened great promise in terms of supporting multi-tissue compartmentalization and predetermined cell commitment. In this review, we offer a critical appraisal on the latest advances in MEW and its convergence with other biofabrication technologies for DOC tissue regeneration. We first present the engineering principles of MEW and the most relevant design aspects for transition from flat to more anatomically relevant 3D structures while printing highly-ordered constructs. Secondly, we provide a thorough assessment of contemporary achievements using MEW scaffolds to study and guide soft and hard tissue regeneration, and draw a parallel on how to extrapolate proven concepts for applications in DOC tissue regeneration. Finally, we offer a combined engineering/clinical perspective on the fabrication of hierarchically organized MEW scaffold architectures and the future translational potential of site-specific, single-step scaffold fabrication to address tissue and tissue interfaces in dental, oral, and craniofacial regenerative medicine. STATEMENT OF SIGNIFICANCE: Melt electrowriting (MEW) techniques can further replicate the complexity of native tissues and could be the foundation for novel personalized (defect-specific) and tissue-specific clinical approaches in regenerative dental medicine. This work presents a unique perspective on how MEW has been translated towards the application of highly-ordered personalized multi-scale and functional interfaces for tissue regeneration, targeting the transition from flat to anatomically-relevant three-dimensional structures. Furthermore, we address the value of convergence of biofabrication technologies to overcome the traditional manufacturing limitations provided by multi-tissue complexity. Taken together, this work offers abundant engineering and clinical perspectives on the fabrication of hierarchically MEW architectures aiming towards site-specific implants to address complex tissue damage in regenerative dental medicine.

Fat grafting in autologous breast reconstruction: applications, outcomes, safety, and complications

Autologous fat grafting is an important surgical technique in aesthetic and reconstructive procedures. Fat grafting for breast reconstruction is now an established procedure for adding volume and improving cutaneous pliability; it can be used independently to replace more invasive flap procedures or implants, or as an adjunct for smaller volume supplementation. The breadth of applications in the breast necessitates diversity in technique and approach, and while there is no universally agreed-upon protocol, basic principles have guided the evolution of some commonly adopted tenets. Broadly, fat grafting outcomes are highly favorable but dependent on patient and procedure factors, requiring learned patient selection and expertise in recipient site assessment. Common complications from fat grafting, such as fat necrosis and the development of nodules, are particularly troublesome for post-oncologic patients, requiring considerable pre-surgical consultation for patient education and managing expectations. In addition to volume and contour augmentation, fat grafting has additional beneficial effects that have recently drawn increased attention including pain reduction from implant capsular contracture or post-mastectomy pain syndrome, improved skin quality and reduced fibrosis following radiation, and possible anti-tumorigenic effects. New developments in clinical fat grafting research that are promising include the use of adipose progenitor cells admixed with lipoaspirate for improved volume retention or alternative biologics such as platelet-rich plasma. Preclinically, research towards safe and effective regenerative medicine approaches is actively underway, with the ultimate goal of achieving predictable and increased graft retention, reducing the number of required surgical procedures and enabling on-table results to reflect procedure outcomes.

Combined Approaches Leading to Synergistic Therapeutic Effects in Spinal Cord Injury: State of the Art.

Cell-based regenerative medicine approaches and motor rehabilitation are currently being used to overcome the consequences of spinal cord injury (SCI). However, their success in preclinical studies does not always translate into successful implementation in clinical practice. Recent work suggests that modern neuromodulation approaches hold great therapeutic promise. Despite these advances, the complete resolution of functional deficits caused by SCI is impossible, especially in cases of severe injury. Therefore, combined approaches based on cell transplantation and neuromodulation are needed to enhance the neuroregenerative effect. The additional inclusion of a dosed locomotor load in the overall therapeutic plan and against a background of combined approaches can have a significant supportive effect. The aim of this review is to evaluate studies that use combinations of different approaches, thereby advancing our current understanding of the mechanisms that underlie their therapeutic effect. This review will consider mostly the effects and limitations of regenerative approaches, as well as the effects of locomotor load and neuromodulation on molecular and cellular changes in the spinal cord.

Ethical and regulatory issues of stem cell-derived 3-dimensional organoid and tissue therapy for personalised regenerative medicine

BackgroundRegenerative medicine has the potential to treat genetic disorders and replace damaged or missing tissue. The use of donor or animal tissue raises many well-known issues, including limited tissue availability, the possibility of rejection and patient infection. Stem cell therapy raised hope of overcoming these issues, but created new risks including tumour formation and limited benefit if the desired target tissue does not form. The recent development of 3-dimensional tissues, including organoids, allows the creation of more complex tissues for personalised regenerative medicine.MethodsThis article details the potential health risks of 3-dimensional organoid and tissue therapy versus dissociated stem cell therapy. The current ethical and regulatory issues surrounding 3-dimensional organoid and tissue therapy are presented with a focus on the highly influential FDA and International Society of Stem Cell Research (ISSCR) guidelines.ConclusionsThe potential use of 3-dimensional organoid and tissue therapy may deliver greater patient benefits than other regenerative medicine approaches, but raises new health and ethical risks. Preclinical testing of these therapies will not mitigate some of their risks; they may only be understood after first-in-human trials. The potential irreversibility and high risk of these therapies affects how clinical trials should be structured, including post-trial care for participants.

Sterilization effects on poly(glycerol dodecanedioate): A biodegradable shape memory elastomer for biomedical applications.

Biodegradable shape memory polymers provide unique regenerative medicine approaches in minimally invasive surgeries. Once heated, thermally responsive shape memory polymer devices can be compressed, programmed to fit within a small profile, delivered in the cold programmed state, and expanded when heated to body temperature. We have previously developed a biodegradable shape memory elastomer (SME), poly(glycerol dodecanedioate) (PGD), with transition temperatures near 37°C exhibiting nonlinear elastic properties like numerous soft tissues. Using SMEs in the clinic requires disinfection and sterilization methods that conserve physiochemical, thermomechanical, and shape recovery properties. We evaluated disinfection protocols using 70% ethanol and UV254 nm for research applications and ethylene oxide (EtO) gas sterilization for clinical applications. Samples disinfected with ethanol for 0.5 and 1 min showed no changes in physiochemical material properties, but after 15 min showed slower recovery rates than controls (p < .05). EtO sterilization at 54.4°C decreased transition temperatures and shape recovery rate compared to EtO sterilization at 37.8°C (p < .01) and controls (p < .05). Aging samples for 9 months in a vacuum desiccator significantly reduced shape recovery, and the recovery rate in EtO sterilized samples compared to controls (p < .001). Cytotoxicity testing (ISO-10993.5C:2012) revealed media extractions from EtO sterilized samples, sterilized at 37.8°C, and high-density polyethylene negative control samples exhibit lower cytotoxicity (IC50) than Ethanol 1min, UV 2h, and EtO 54.4°C. Cell viability of NIH3T3 fibroblasts on sterilized surfaces was equivalent on EtO 37.7°C, EtO 54.4°C and Ethanol sterilized substrates. Finally, chromogenic bacterial endotoxin testing showed endotoxin levels were below the FDA prescribed levels for devices contacting blood and lymphatic tissues for ethanol 1min, UV 120 min, EtO 37.7°C, EtO 54.4°C. These findings outline various disinfection and sterilization processes for research and pre-clinical application and provide a pathway for developing custom sterilization cycles for the translation of biomedical devices utilizing PGD shape memory polymers.

Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches

Nowadays, the real need in orthopedic research is to strictly validate advanced regenerative medicine approaches in preclinical models, with the hope that this unique and straightforward approach can facilitate a safe and effective translation into everyday clinical practice [...].

Comparative Efficiency of Gene-Activated Matrices Based on Chitosan Hydrogel and PRP Impregnated with BMP2 Polyplexes for Bone Regeneration

Gene therapy is one of the most promising approaches in regenerative medicine. Gene-activated matrices provide stable gene expression and the production of osteogenic proteins in situ to stimulate osteogenesis and bone repair. In this study, we developed new gene-activated matrices based on polylactide granules (PLA) impregnated with BMP2 polyplexes and included in chitosan hydrogel or PRP-based fibrin hydrogel. The matrices showed high biocompatibility both in vitro with mesenchymal stem cells and in vivo when implanted intramuscularly in rats. The use of porous PLA granules allowed the inclusion of a high concentration of polyplexes, and the introduction of the granules into hydrogel provided the gradual release of the plasmid constructs. All gene-activated matrices showed transfecting ability and ensured long-term gene expression and the production of target proteins in vitro. At the same time, the achieved concentration of BMP-2 was sufficient to induce osteogenic differentiation of MSCs. When implanted into critical-size calvarial defects in rats, all matrices with BMP2 polyplexes led to new bone formation. The most significant effect on osteoinduction was observed for the PLA/PRP matrices. Thus, the developed gene-activated matrices were shown to be safe and effective osteoplastic materials. PLA granules and PRP-based fibrin hydrogel containing BMP2 polyplexes were shown to be the most promising for future applications in bone regeneration.

Active inference, morphogenesis, and computational psychiatry.

Active inference is a leading theory in neuroscience that provides a simple and neuro-biologically plausible account of how action and perception are coupled in producing (Bayes) optimal behavior; and has been recently used to explain a variety of psychopathological conditions. In parallel, morphogenesis has been described as the behavior of a (non-neural) cellular collective intelligence solving problems in anatomical morphospace. In this article, we establish a link between the domains of cell biology and neuroscience, by analyzing disorders of morphogenesis as disorders of (active) inference. The aim of this article is three-fold. We want to: (i) reveal a connection between disorders of morphogenesis and disorders of active inference as apparent in psychopathological conditions; (ii) show how disorders of morphogenesis can be simulated using active inference; (iii) suggest that active inference can shed light on developmental defects or aberrant morphogenetic processes, seen as disorders of information processing, and perhaps suggesting novel intervention and repair strategies. We present four simulations illustrating application of these ideas to cellular behavior during morphogenesis. Three of the simulations show that the same forms of aberrant active inference (e.g., deficits of sensory attenuation and low sensory precision) that have been used to explain psychopathological conditions (e.g., schizophrenia and autism) also produce familiar disorders of development and morphogenesis when implemented at the level of the collective behavior of a group of cells. The fourth simulation involves two cells with too high precision, in which we show that the reduction of concentration signaling and sensitivity to the signals of other cells treats the development defect. Finally, we present the results of an experimental test of one of the model's predictions in early Xenopus laevis embryos: thioridazine (a dopamine antagonist that may reduce sensory precision in biological systems) induced developmental (anatomical) defects as predicted. The use of conceptual and empirical tools from neuroscience to understand the morphogenetic behavior of pre-neural agents offers the possibility of new approaches in regenerative medicine and evolutionary developmental biology.

Therapeutic potential of adipose tissue-derivatives in modern dermatology.

Stem cell-mediated therapies in combination with biomaterial and growth factor-based approaches in regenerative medicine are rapidly evolving with increasing application beyond the dermatologic field. Adipose-derived stem cells (ADSCs) are the more frequently used adult stem cells due to their abundance and easy access. In the case of volumetric defects, adipose tissue can take the shape of defects, restoring the volume and enhancing the regeneration of receiving tissue. When regenerative purposes prevail on volume restoration, the stromal vascular fraction (SVF) rich in staminal cells, purified mesenchymal stem cells (MSCs) or their cell-free derivatives grafting are favoured. The therapeutic efficacy of acellular approaches is explained by the fact that a significant part of the natural propensity of stem cells to repair damaged tissue is ascribable to their secretory activity that combines mitogenic factors, cytokines, chemokines and extracellular matrix components. Therefore, the secretome's ability to modulate multiple targets simultaneously demonstrated preclinical and clinical efficacy in reversing pathological mechanisms of complex conditions such atopic dermatitis (AD), vitiligo, psoriasis, acne and Lichen sclerosus (LS), non-resolving wounds and alopecia. This review analysing bothin vivoandin vitromodels gives an overview of the clinical relevance of adipose tissue-derivatives such as autologous fat graft, stromal vascular fraction, purified stem cells and secretome for skin disorders application. Finally, we highlighted the major disease-specific limitations and the future perspective in this field.

Meet the First Authors.

HomeCirculation ResearchVol. 131, No. 10Meet the First Authors Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Authors Originally published27 Oct 2022https://doi.org/10.1161/RES.0000000000000580Circulation Research. 2022;131:790–791Sox17 Deficiency Promotes PAH via c-Met Activation (p 792)Download figureDownload PowerPointDr Chan Soon Park is a clinical fellow in the Division of Cardiology at Seoul National University Hospital (SNUH). He earned his BS and MS in Medicine from Seoul National University and his PhD in Medical Science and Engineering from Korea Advanced Institute of Science and Technology (KAIST). During the PhD program in Graduate School of Medical Science and Engineering in KAIST, he was able to learn basic and translational research, the importance of which has been increasingly emphasized in the development of novel and clinically relevant therapeutic strategies in the field of cardiology. Dr Park continues to expand his research in the roles of endothelial cells in various cardiovascular diseases (CVDs) beyond pulmonary arterial hypertension. He also has interests in clinical research, including the association between metabolic profiles and CVDs as well as the role of imaging in CVD risk stratification. Outside of work, he enjoys hiking and spending time with his family.Prohibitin2 Maintains VSMC Contractile Phenotype (p 807)Download figureDownload PowerPointDr Yiting Jia is a postdoctoral fellow at Peking University Health Science Center (PI: Dr Wei Kong and Dr Caihong Yun). He earned his PhD from Peking University. His early experience in research was focused on metabolism reprogramming, lysosome biology and cardiovascular diseases. Now he is gearing up to become an independent research investigator. Outside of work, he enjoys soccer, tennis and listening to music.Download figureDownload PowerPointDr Chenfeng Mao is a research associate at the Beijing Institute of Biotechnology in Beijing, China. He earned a PhD in human physiology from the Department of Physiology and Pathophysiology in Peking University (mentor, Dr Wei Kong). His research focuses on extracellular matrix microenvironment on vascular remodeling during physiological and disease state. Outside of work he enjoys playing badminton.MED1, BMP/TGF-β and Pulmonary Hypertension (p 828)Download figureDownload PowerPointDr Chen Wang earned her PhD from Xi’ an Jiaotong University. During her PhD studies, she was also trained in the laboratory of Dr Ingrid Fleming at the Institute of Vascular Research, Goethe University. Her research focuses on endothelial dysfunction involved in vascular diseases. She was awarded the “Paul Dudley White International Scholar” from ATVB in 2022 and has published several first-author papers including in Circulation and Circulation Research. Her career goal is to become a physician scientist working on cardiovascular diseases and related translational research. Outside of work, she enjoys traveling, music and baking.Download figureDownload PowerPointYuanming Xing is a PhD candidate in internal medicine at Xi’an Jiaotong University. She also studied computational biology at Warshel Institute for Computational Biology at the Chinese University of Hong Kong-Shenzhen. She is interested in endothelial function in cardiovascular diseases and has published several papers in the related fields. Her career plan is to become a physician who is also proficient in computational biology. She enjoys learning new things, especially what she may not be good at. In her spare time, she has a passion for animal rescue, computer programming and painting.Intrapericardial Exosomes Repair Heart via Foxo3 (p e135)Download figureDownload PowerPointDr Dashuai Zhu is a postdoctoral research fellow in the BioTherapeutics Lab, headed by Dr Ke Cheng (UNC Chapel Hill and North Carolina State University). Dashuai earned his PhD from the Nankai University, China, where he started his career on cardiac repair using tissue engineering and biomedical engineering approaches. His research focuses on regenerative medicine approaches for the treatment of heart disease, with a particular interest in cell and cell-free therapies for myocardial infarction and heart failure. He can be found on Twitter @das_zhu.Download figureDownload PowerPointDr Ke Huang is an assistant research professor in the Department of Molecular Biomedical Sciences at North Carolina State University. He earned his MD in 2008 from Shanxi Medical University and PhD from North Carolina State University. His postdoctral training was at Duke University. His research focuses on regenerative medicine strategies with a particular interest in adult stem cells, biomaterials and nanomedicine approaches. He can be found on [email protected] Previous Back to top Next FiguresReferencesRelatedDetails October 28, 2022Vol 131, Issue 10 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000580PMID: 36302055 Originally publishedOctober 27, 2022 PDF download Advertisement SubjectsAgingCardiovascular DiseaseExercise

A 3D printed mimetic composite for the treatment of growth plate injuries in a rabbit model

Growth plate injuries affecting the pediatric population may cause unwanted bony repair tissue that leads to abnormal bone elongation. Clinical treatment involves bony bar resection and implantation of an interpositional material, but success is limited and the bony bar often reforms. No treatment attempts to regenerate the growth plate cartilage. Herein we develop a 3D printed growth plate mimetic composite as a potential regenerative medicine approach with the goal of preventing limb length discrepancies and inducing cartilage regeneration. A poly(ethylene glycol)-based resin was used with digital light processing to 3D print a mechanical support structure infilled with a soft cartilage-mimetic hydrogel containing chondrogenic cues. Our biomimetic composite has similar mechanical properties to native rabbit growth plate and induced chondrogenic differentiation of rabbit mesenchymal stromal cells in vitro. We evaluated its efficacy as a regenerative interpositional material applied after bony bar resection in a rabbit model of growth plate injury. Radiographic imaging was used to monitor limb length and tibial plateau angle, microcomputed tomography assessed bone morphology, and histology characterized the repair tissue that formed. Our 3D printed growth plate mimetic composite resulted in improved tibial lengthening compared to an untreated control, cartilage-mimetic hydrogel only condition, and a fat graft. However, in vivo the 3D printed growth plate mimetic composite did not show cartilage regeneration within the construct histologically. Nevertheless, this study demonstrates the feasibility of a 3D printed biomimetic composite to improve limb lengthening, a key functional outcome, supporting its further investigation as a treatment for growth plate injuries.

Isolation of ready-made rat microvessels and its applications in effective in vivo vascularization and in angiogenic studies in vitro.

Despite recent advances in the differentiation of human pluripotent stem cells into multiple cell types for application in replacement therapies, tissue vascularization remains a bottleneck for regenerative medicine. Fragments of primary microvessels (MVs) harvested from adipose tissue retain endothelialized lumens and perivascular cell coverage. We have used these MVs to support the survival and engraftment of transplanted human pluripotent stem cell-derived cardiomyocytes, pancreatic progenitors or primary human islets. MVs connect with host vessels, perfuse with blood and form a hierarchal vascular network in vivo after subcutaneous or intracardiac transplantation. MVs also display the ability to remodel and form stable vascular networks with long-term retention (>3.5 months). MVs can be cultured in 3D hydrogels in vitro, where they retain vessel shape and undergo angiogenic sprouting without the need for exogenous growth factor supplementation. Therefore, MVs offer a robust vascularization strategy for regenerative medicine approaches and a platform for angiogenic studies and drug testing in vitro. Here we describe in detail the protocol for: (1) the isolation of MVs from rat epididymal fat by limited collagenase digestion, followed by size-selective sieving; (2) the incorporation of MVs into 3D collagen hydrogels; (3) the in vitro culture of MVs in 3D gels for angiogenic studies; and (4) the in vivo transplantation of 3D hydrogels containing MVs into the mouse subcutis. The isolation procedure does not require highly specific equipment and can be performed in ~3 h by researchers with experience in rodent handling and cell culture.