Research and clinical translation of trilayer stent-graft of expanded polytetrafluoroethylene for interventional treatment of aortic dissection

The aortic dissection(AD)is a life-threatening disease.The transcatheter endovascular aortic repair(EVAR)affords a minimally invasive technique to save the lives of these critical patients,and an appropriate stent-graft gets to be the key medical device during an EVAR procedure.Herein,we report a trilayer stent-graft and corresponding delivery system used for the treatment of the AD disease.The stent-graft is made of nitinol stents with an asymmetric Z-wave design and two expanded polytetrafluoroethylene(ePTFE)membranes.Each of the inner and outer surfaces of the stent-graft was covered by an ePTFE membrane,and the two membranes were then sintered together.The biological studies of the sintered ePTFE membranes indicated that the stent-graft had excellent cytocompatibility and hemocompatibility in vitro.Both the stent-graft and the delivery system exhibited satisfactory mechanical properties and operability.The safety and efficacy of this stent-graft and the corresponding delivery system were demonstrated in vivo.In nine canine experiments,the blood vessels of the animals implanted with the stent-grafts were of good patency,and there were no thrombus and obvious stenosis by angiography after implantation for 6months.Furthermore,all of the nine clinical cases experienced successful implantation using the stent-graft and its postrelease delivery system,and the 1-year follow-ups indicated the preliminary safety and efficacy of the trilayer stent-graft with an asymmetric Z-wave design for interventional treatment.

Current approaches of nanomedicines in the market and various stage of clinical translation

Compared with traditional drug therapy,nanomedicines exhibit intriguing biological features to increase therapeutic efficiency,reduce toxicity and achieve targeting delivery.This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials,which manifests a diversified trend in carrier types,applied indications and mechanisms of action.From the perspective of indications,this article presents an overview of the applications of nanomedicines involving the prevention,diagnosis and treatment of various diseases,which include cancer,infections,blood disorders,cardiovascular diseases,immuno-associated diseases and nervous system diseases,etc.Moreover,the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.

Update on the research and development of magnesium-based biodegradable implants and their clinical translation in orthopaedics

Biodegradable magnesium(Mg)or its alloys are desirable materials for development into new-generation internal fixation devices or implants with high biocompatibility,adequate mechanical modulus,and osteopromotive properties,which may overcome some of the drawbacks of the existing permanent orthopaedic implants with regard to stress-shielding of bone and beam-hardening effects on radiographic images.This review summarises the current research status of Mg-based orthopaedic implants in animals and clinical trials.First,detailed information of animal studies including bone fracture repair and anterior cruciate ligament reconstruction with the use of Mg-based orthopaedic devices is introduced.Second,the repair mechanisms of the Mg-based orthopaedic implants are also reviewed.Afterwards,reports of recent clinical cases treated using Mg-based implants in orthopaedics are summarised.Finally,the challenges and the strategies of the use of Mg-based orthopaedic implants are discussed.Taken together,the collected efforts in basic research,translational work,and clinical applications of Mg-based orthopaedic implants over the last decades greatly contribute to the development of a new generation of biodegradable metals used for the design of innovative implants for better treatment of orthopaedic conditions in patients with challenging skeletal disorders or injuries.

Current trends and key considerations in the clinical translation of targeted fluorescent probes for intraoperative navigation

The rapid development of fluorescence imaging for intraoperative navigation has spurred further development of targeted fluorescent probes in the past decade.Only a few nontargeted dyes,including indocyanine green and methylene blue,are currently applied for fluorescence guided surgery in the clinic.While no targeted fluorescent probes have been approved for the clinic,a number of them have entered clinical trials.These probes have emission wavelengths in the visible and near infrared(NIR)-I(700-900 nm)range.Among them,activatable probes and nanoprobes have generated special interest.Compared with NIR-I fluorescent probes,NIR-II(1000-1700 nm)fluorescent probes exhibit better intravital performance in terms of increased penetration depths,reduced tissue autofluorescence,and higher signalto-background ratios.However,more challenges are expected before the successful translation of NIR-II probes from bench to bedside.This review provides a brief overview of targeted fluorescent probes under clinical evaluation and recent achievements in the field of NIR-II fluorescence imaging.In addition,we outline key considerations concerning the design of fluorescent probes for clinical translation.

Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium:Integration of herbal medicine,enzyme engineering,and nanotechnology

Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium(EF)and possess excellent therapeutic effects on various diseases.Encouragingly,in 2022,icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma(HCC)by National Medical Products Administration(NMPA)of China.Moreover,recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects.Nonetheless,both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content,poor bioavailability,and unfavorable in vivo delivery efficiency.Recently,various strategies,including enzyme engineering and nanotechnology,have been developed to increase productivity and activity,improve delivery efficiency,and enhance therapeutic effects of epimedium flavonoids.In this review,the structure-activity relationship of epimedium flavonoids is described.Then,enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed.The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized.Finally,the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.

Nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma(HCC),such as surgical resection,transplantation,radiofrequency ablation,and chemotherapy are unsatisfactory,and therefore the exploration of powerful therapeutic strategies is urgently needed.Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects.Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC.Encouragingly,in 2022,icaritin soft capsules were approved by the National Medical Products Administration(NMPA)of China for the immunotherapy of advanced HCC.However,the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency.Recently,functionalized drug delivery systems including stimuli-responsive nanocarriers,cell membrane-coated nanocarriers,and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs,including the low bioavailability and limited delivery efficiency as well as side effects.Taken together,the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC.Herein,we compared the different preparation methods for icaritin,interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC,and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritinbased nanomedicines for advanced HCC immunotherapy.Finally,the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

Cardiac resident macrophages: Spatiotemporal distribution, development, physiological functions, and their translational potential on cardiac diseases

Cardiac resident macrophages (CRMs) are the main population of cardiac immune cells. The role of these cells in regeneration, functional remodeling, and repair after cardiac injury is always the focus of research. However, in recent years, their dynamic changes and contributions in physiological states have a significant attention. CRMs have specific phenotypes and functions in different cardiac chambers or locations of the heart and at different stages. They further show specific differentiation and development processes. The present review will summarize the new progress about the spatiotemporal distribution, potential developmental regulation, and their roles in cardiac development and aging as well as the translational potential of CRMs on cardiac diseases. Of course, the research tools for CRMs, their respective advantages and disadvantages, and key issues on CRMs will further be discussed.

Bone Regeneration Based on Tissue Engineering Conceptions – A 21st Century Perspective

The role of Bone Tissue Engineering in the field of Regenerative Medicine has been the topic of substantial research over the past two decades. Technological advances have improved orthopaedic implants and surgical techniques for bone reconstruction. However, improvements in surgical techniques to reconstruct bone have been limited by the paucity of autologous materials available and donor site morbidity. Recent advances in the development of biomaterials have provided attractive alternatives to bone grafting expanding the surgical options for restoring the form and function of injured bone. Specifically, novel bioactive （second generation） biomaterials have been developed that are characterised by controlled action and reaction to the host tissue environment, whilst exhibiting controlled chemical breakdown and resorption with an ultimate replacement by regenerating tissue. Future generations of biomaterials （third generation） are designed to be not only osteo- conductive but also osteoinductive, i.e. to stimulate regeneration of host tissues by combining tissue engineer- ing and in situ tissue regeneration methods with a focus on novel applications. These techniques will lead to novel possibilities for tissue regeneration and repair. At present, tissue engineered constructs that may find future use as bone grafts for complex skeletal defects, whether from post-traumatic, degenerative, neoplastic or congenital/developmental ＂origin＂ require osseous reconstruction to ensure structural and functional integrity. Engineering functional bone using combinations of cells, scaffolds and bioactive factors is a promising strategy and a particular feature for future development in the area of hybrid materials which are able to exhibit suitable biomimetic and mechanical properties. This review will discuss the state of the art in this field and what we can expect from future generations of bone regeneration concepts.

Large animal ischemic stroke models: replicating human stroke pathophysiology

The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions.Although promising therapeutics have been identified using these animal models,with most undergoing significant testing in rodent models,the vast majority of these interventions have failed in human clinical trials.This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models.Large animal models such as non-human primates,sheep,pigs,and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline.The objective of this review is to highlight key characteristics that potentially make these gyrencephalic,large animal ischemic stroke models more predictive by comparing pathophysiological responses,tissue-level changes,and model limitations.

Functionalized Hydrogels for Articular Cartilage Tissue Engineering

Articular cartilage(AC)is an avascular and flexible connective tissue located on the bone surface in the diarthrodial joints.AC defects are common in the knees of young and physically active individuals.Because of the lack of suitable tissue-engineered artificial matrices,current therapies for AC defects,espe-cially full-thickness AC defects and osteochondral interfaces,fail to replace or regenerate damaged carti-lage adequately.With rapid research and development advancements in AC tissue engineering(ACTE),functionalized hydrogels have emerged as promising cartilage matrix substitutes because of their favor-able biomechanical properties,water content,swelling ability,cytocompatibility,biodegradability,and lubricating behaviors.They can be rationally designed and conveniently tuned to simulate the extracel-lular matrix of cartilage.This article briefly introduces the composition,structure,and function of AC and its defects,followed by a comprehensive review of the exquisite(bio)design and(bio)fabrication of func-tionalized hydrogels for AC repair.Finally,we summarize the challenges encountered in functionalized hydrogel-based strategies for ACTE both in vivo and in vitro and the future directions for clinical translation.

Precision medicine: In need of guidance and surveillance

Precision medicine,currently a hotspot in mainstream medicine,has been strongly promoted in recent years. With rapid technological development,such as next-generation sequencing,and fierce competition in molecular targeted drug exploitation,precision medicine represents an advance in science and technology; it also fulfills needs in public health care. The clinical translation and application of precision medicine-especially in the prevention and treatment of tumors-is far from satisfactory; however,the aims of precision medicine deserve approval. Thus,this medical approach is currently in its infancy; it has promising prospects,but it needs to overcome numbers of problems and deficiencies. It is expected that in addition to conventional symptoms and signs,precision medicine will define disease in terms of the underlying molecular characteristics and other environmental susceptibility factors. Those expectations should be realized by constructing a novel data network,integrating clinical data from individual patients and personal genomic background with existing research on the molecular makeup of diseases. In addition,multi-omics analysis and multi-discipline collaboration will become crucial elements in precision medicine. Precision medicine deserves strong support,and its development demands directed momentum. We propose three kinds of impetus(research,application and collaboration impetus) for such directed momentum toward promoting precision medicine and accelerating its clinical translation and application.

Recent Progress in Cartilage Tissue Engineering--Our Experience and Future Directions

Given the limited spontaneous repair that follows cartilage injury, demand is growing for tissue engi- neering approaches for cartilage regeneration. There are two major applications for tissue-engineered cartilage. One is in orthopedic surgery, in which the engineered cartilage is usually used to repair cartilage defects or loss in an articular joint or meniscus in order to restore the joint function. The other is for head and neck reconstruction, in which the engineered cartilage is usually applied to repair cartilage defects or loss in an auricle, trachea, nose, larynx, or eyelid. The challenges faced by the engineered car- tilage for one application are quite different from those faced by the engineered cartilage for the other application. As a result, the emphases of the engineering strategies to generate cartilage are usually quite different for each application. The statuses of preclinical animal investigations and of the clinical translation of engineered cartilage are also at different levels for each application. The aim of this review is to provide an opinion piece on the challenges, current developments, and future directions for cartilage engineering for both applications.

Modulating microRNAs in cancer: next-generation therapies

MicroRNAs(miRNAs)are a class of endogenously expressed non-coding regulators of the genome with an ability to mediate a variety of biological and pathological processes.There is growing evidence demonstrating frequent dysregulation of microRNAs in cancer cells,which is associated with tumor initiation,development,migration,invasion,resisting cell death,and drug resistance.Studies have shown that modulation of these small RNAs is a novel and promising therapeutic tool in the treatment of a variety of diseases,especially cancer,due to their broad influence on multiple cellular processes.However,suboptimal delivery of the appropriate miRNA to the cancer sites,quick degradation by nucleases in the blood circulation,and off target effects have limited their research and clinical applications.Therefore,there is a pressing need to improve the therapeutic efficacy of miRNA modulators,while at the same time reducing their toxicities.Several delivery vehicles for miRNA modulators have been shown to be effective in vitro and in vivo.In this review,we will discuss the role and importance of miRNAs in cancer and provide perspectives on currently available carriers for miRNA modulation.We will also summarize the challenges and prospects for the clinical translation of miRNAbased therapeutic strategies.

The clinical prospect of FLASH radiotherapy

FLASH radiotherapy(FLASH-RT)is a new strategy for tumor treatment with an ultra-high dose rate of more than 40 Gy/s.Compared with conventional radiotherapy(CONV-RT),FLASH-RT has no different inhibitory effects on tumors but less damage to normal tissues,which is called the“spare”effect.The“spare”effect triggers our exploration of the great prospect of subverting conventional radiotherapy and its intricate mechanisms.Mitochondrial homeostasis,the immune microenvironment,or DNA integrity may potentially represent the primary breakthrough direction in understanding the mechanisms.Concurrently,it is imperative to advance timely clinical translation efforts.Clinical trials of FLASH-RT have progressed to Phase II in both the United States and Switzerland,with current findings suggesting that FLASH-RT achieves comparable efficacy to CONV-RT while mitigating side effects in select cancer cell types.While summarizing the existing FLASH experiments,this paper emphasizes the significance of clinical transformation and the challenges that will be faced and proposes possible solutions.

Pseudotyped lentiviral vectors:Ready for translation into targeted cancer gene therapy?

Gene therapy holds great promise for curing cancer by editing the deleterious genes of tumor cells,but the lack of vector systems for efficient delivery of genetic material into specific tumor sites in vivo has limited its full therapeutic potential in cancer gene therapy.Over the past two decades,increasing studies have shown that lentiviral vectors(LVs)modified with different glycoproteins from a donating virus,a process referred to as pseudotyping,have altered tropism and display cell-type specificity in transduction,leading to selective tumor cell killing.This feature of LVs together with their ability to enable high efficient gene delivery in dividing and non-dividing mammalian cells in vivo make them to be attractive tools in future cancer gene therapy.This review is intended to summarize the status quo of some typical pseudotypings of LVs and their applications in basic anti-cancer studies across many malignancies.The opportunities of translating pseudotyped LVs into clinic use in cancer therapy have also been discussed.

Essential neural anatomy for creating a clinically translatable osseointegrated neural interface for prosthetic control in sheep

Aim:Ovine models for osseointegrated prosthetics research are well established,but do not consider neural control of advanced prostheses.The validity of interfacing technologies,such as the Osseointegrated Neural Interface(ONI),in their ability to provide communication between native nerves and advanced prosthetics is required,necessitating a stable,longitudinal large animal model for testing.The objective of this study is to provide a detailed anatomic description of the major nerves distal to the carpal and tarsal joints,informing the creation of a chronic ONI for prosthetic control in sheep.Methods:Six pelvic and six thoracic cadaveric limbs from mature female,non-lactating sheep were utilized.Radiographs were obtained to determine average bone length,medullary canal diameter,and cortical bone thickness.Microsurgical dissection was performed to discern topographical neuroanatomy and average circumferences of the major nerves of the pelvic and thoracic limbs.Histologic analysis was performed.A surgical approach for the creation of ONI was designed.Results:Average metacarpal and metatarsal length was 15.0 cm(±0.0)and 19.7 cm(±1.0),respectively.Average intramedullary canal diameter was 12.91 mm(±3.69)for forelimbs and 12.60 mm(±3.69)for hindlimbs.The thoracic limb nerves consisted of one dorsal and three ventral nerves,with an average circumference of 5.14 mm(±2.00)and 5.05 mm(±1.06),respectively.Pelvic limb nerves consisted of two dorsal and one ventral nerve with an average circumference of 6.27 mm(±1.79)and 5.40 mm(±0.53),respectively.Conclusions:These anatomic data inform the surgical approach and manufacture of a sensory ONI for chronic testing in awake,freely ambulating animals for future clinical translation.

Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis

Doxorubicin(DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients,but related pharmacotherapeutic measures are relatively limited.Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity.Idebenone,a novel ferroptosis inhibitor,is a well-described clinical drug widely used.However,its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear.In this study,we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism.A single intraperitoneal injection of DOX(15 mg/kg)was administrated to establish DOX-induced cardiotoxicity.The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe^(2+)and ROS overload,which resulted in ferroptosis.CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1.Interestingly,idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX.Idebenone could form stable hydrogen bonds with FSP1 protein at K355,which may influence its association with ubiquitin.The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation.In conclusion,this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1,making it a potential clinical drug for patients receiving DOX treatment.

New idea to promote the clinical applications of stem cells or their extracellular vesicles in central nervous system disorders:Combining with intranasal delivery

The clinical translation of stem cells and their extracellular vesicles(EVs)-based therapy for central nervous system(CNS) diseases is booming. Nevertheless, the insufficient CNS delivery and retention together with the invasiveness of current administration routes prevent stem cells or EVs from fully exerting their clinical therapeutic potential. Intranasal(IN) delivery is a possible strategy to solve problems as IN route could circumvent the brain-blood barrier non-invasively and fit repeated dosage regimens. Herein, we gave an overview of studies and clinical trials involved with IN route and discussed the possibility of employing IN delivery to solve problems in stem cells or EVs-based therapy. We reviewed relevant researches that combining stem cells or EVs-based therapy with IN administration and analyzed benefits brought by IN route. Finally, we proposed possible suggestions to facilitate the development of IN delivery of stem cells or EVs.

Advances and perspective on the translational medicine of biodegradable metals

Biodegradable metals,designed to be safely degraded and absorbed by the body after fulfil the intended functions,are of particular interest in the 21st century.The marriage of advanced biodegradable metals with clinical needs have yield unprecedented possibility.Magnesium,iron,and zinc-based materials constitute the main components of temporary,implantable metallic medical devices.A burgeoning number of studies on biodegradable metals have driven the clinical translation of biodegradable metallic devices in the fields of cardiology and orthopaedics over the last decade.Their ability to degrade as well as their beneficial biological functions elicited during degradation endow this type of material with the potential to shift the paradigm in the treatment of musculoskeletal and cardiovascular diseases.This review provides an insight into the degradation mechanism of these metallic devices in specific application sites and introduces state-of-the-art translational research in the field of biodegradable metals,as well as highlighting some challenges for materials design strategies in the context of mechanical and biological compatibility.

Article Preclinical evaluation of acute systemic toxicity of magnesium incorporated poly(lactic-co-glycolic acid)porous scaffolds by three-dimensional printing Jing

Biodegradable polymer scaffolds combined with bioactive components which accelerate osteogenesis and angiogenesis have promise for use in clinical bone defect repair.The preclinical acute toxicity evaluation is an essential assay of implantable biomaterials to assess the biosafety for accelerating clinical translation.We have successfully developed magnesium(Mg)particles and beta-tricalcium phosphate(β-TCP)for incorporation into poly(lactic-co-glycolic acid)(PLGA)porous composite scaffolds(PTM)using low-temperature rapid prototyping three-dimensional-printing technology.The PTM scaffolds have been fully evaluated and found to exhibit excellent osteogenic capacity for bone defect repair.The preclinical evaluation of acute systemic toxicities is essential and important for development of porous scaffolds to facilitate their clinical translation.In this study,acute systemic toxicity of the PTM scaffolds was evaluated in mice by intraperitoneal injection of the extract solutions of the scaffolds.PTM composite scaffolds with different Mg andβ-TCP content(denoted as PT5M,PT10M,and PT15M)were extracted with different tissue culture media,including normal saline,phosphate-buffered saline,and serum-free minimum essential medium,to create the extract solutions.The evaluation was carried out following the National Standard.The acute toxicity was fully evaluated through the collection of extensive data,including serum/organs ion concentration,fluorescence staining,and in vivo median lethal dose measurement.Mg in major organs(heart,liver,and lung),and Mg ion concentrations in serum of mice,after intraperitoneal injection of the extract solutions,were measured and showed that the extract solutions of PT15M caused significant elevation of serum Mg ion concentrations,which exceeded the safety threshold and led to the death of the mice.In contrast,the extract solutions of PT5M and PT10M scaffolds did not cause the death of the injected mice.The median lethal dose of Mg ions in vivo for mice was determined for the first time in this study to be 110.66 mg/kg,and the safety level of serum magnesium toxicity in mice is 5.4 mM,while the calcium serum safety level is determined as 3.4 mM.The study was approved by the Animal Care and Use Committee of Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences(approval No.SIAT-IRB-170401-YGS-LYX-A0346)on April 5,2017.All these results showed that the Mg ion concentration of intraperitoneally-injected extract solutions was a determinant of mouse survival,and a high Mg ion concentration(more than 240 mM)was the pivotal factor contributing to the death of the mice,while changes in pH value showed a negligible effect.The comprehensive acute systemic toxicity evaluation for PTM porous composite scaffolds in this study provided a reference to guide the design and optimization of this composite scaffold and the results demonstrated the preclinical safety of the as-fabricated PTM scaffold with appropriate Mg content,strongly supporting the official registration process of the PTM scaffold as a medical device for clinical translation.