Ultrasound Therapy: Experiences and Perspectives for Regenerative Medicine

Ultrasound has emerged as a novel tool for clinical applications, particularly in the context of regenerative medicine. Due to its unique physico-mechanical properties, low-intensity ultrasound (LIUS) has been approved for accelerated fracture healing and for the treatment of established non-union, but its utility has extended beyond tissue engineering to other fields, including cell regeneration. Cells and tissues respond to acoustic ultrasound by switching on genetic repair circuits, triggering a cascade of molecular signals that promote cell proliferation, adhesion, migration, differentiation, and extracellular matrix production. LIUS also induces angiogenesis and tissue regeneration and has anti-inflammatory and anti-degenerative effects. Accordingly, the potential application of ultrasound for tissue repair/regeneration has been tested in several studies as a stand-alone treatment and, more recently, as an adjunct to cell-based therapies. For example, ultrasound has been proposed to improve stem cell homing to target tissues due to its ability to create a transitional and local gradient of cytokines and chemokines. In this review, we provide an overview of the many applications of ultrasound in clinical medicine, with a focus on its value as an adjunct to cell-based interventions. Finally, we discuss the various preclinical and clinical studies that have investigated the potential of ultrasound for regenerative medicine.

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AR Splicing Variants and Resistance to AR Targeting Agents

Cancers ◽

10.3390/cancers13112563 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2563

Author(s):

Mayuko Kanayama ◽

Changxue Lu ◽

Jun Luo ◽

Emmanuel S. Antonarakis

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Splice Variants ◽

Treatment Options ◽

Predictive Biomarker ◽

Castration Resistant Prostate Cancer ◽

Treatment Benefit ◽

Novel Biomarkers ◽

The Many ◽

Preclinical And Clinical Studies

Over the past decade, advances in prostate cancer research have led to discovery and development of novel biomarkers and effective treatments. As treatment options diversify, it is critical to further develop and use optimal biomarkers for the purpose of maximizing treatment benefit and minimizing unwanted adverse effects. Because most treatments for prostate cancer target androgen receptor (AR) signaling, aberrations affecting this drug target are likely to emerge following the development of castration-resistant prostate cancer (CRPC), and it is conceivable that such aberrations may play a role in drug resistance. Among the many AR aberrations, we and others have been studying androgen receptor splice variants (AR-Vs), especially AR-V7, and have conducted preclinical and clinical studies to develop and validate the clinical utility of AR-V7 as a prognostic and potential predictive biomarker. In this review, we first describe mechanisms of AR-V generation, regulation and their functions from a molecular perspective. We then discuss AR-Vs from a clinical perspective, focusing on the significance of AR-Vs detected in different types of human specimens and AR-Vs as potential therapeutic targets.

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Special Issue: Application of Extracellular Matrix in Regenerative Medicine

Applied Sciences ◽

10.3390/app11073262 ◽

2021 ◽

Vol 11 (7) ◽

pp. 3262

Author(s):

Neill J. Turner

Keyword(s):

Extracellular Matrix ◽

Regenerative Medicine ◽

Wound Repair ◽

Three Dimensional ◽

Dynamic Structure ◽

Scaffold Material ◽

Special Issue ◽

Organ Regeneration ◽

Scaffold Materials ◽

The Many

The present Special Issue comprises a collection of articles addressing the many ways in which extracellular matrix (ECM), or its components parts, can be used in regenerative medicine applications. ECM is a dynamic structure, composed of a three-dimensional architecture of fibrous proteins, proteoglycans, and glycosaminoglycans, synthesized by the resident cells. Consequently, ECM can be considered as nature’s ideal biologic scaffold material. The articles in this Special Issue cover a range of topics from the use of ECM components to manufacture scaffold materials, understanding how changes in ECM composition can lead to the development of disease, and how decellularization techniques can be used to develop tissue-derived ECM scaffolds for whole organ regeneration and wound repair. This editorial briefly summarizes the most interesting aspects of these articles.

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A counter gradient of Activin A and follistatin instructs the timing of hair cell differentiation in the murine cochlea

eLife ◽

10.7554/elife.47613 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Meenakshi Prajapati-DiNubila ◽

Ana Benito-Gonzalez ◽

Erin Jennifer Golden ◽

Shuran Zhang ◽

Angelika Doetzlhofer

Keyword(s):

Cell Differentiation ◽

Hair Cell ◽

Hair Cells ◽

Activin A ◽

Sensory Epithelium ◽

Outer Hair Cells ◽

Longitudinal Gradient ◽

Hair Cell Differentiation ◽

Local Gradient ◽

Molecular Signals

The mammalian auditory sensory epithelium has one of the most stereotyped cellular patterns known in vertebrates. Mechano-sensory hair cells are arranged in precise rows, with one row of inner and three rows of outer hair cells spanning the length of the spiral-shaped sensory epithelium. Aiding such precise cellular patterning, differentiation of the auditory sensory epithelium is precisely timed and follows a steep longitudinal gradient. The molecular signals that promote auditory sensory differentiation and instruct its graded pattern are largely unknown. Here, we identify Activin A and its antagonist follistatin as key regulators of hair cell differentiation and show, using mouse genetic approaches, that a local gradient of Activin A signaling within the auditory sensory epithelium times the longitudinal gradient of hair cell differentiation. Furthermore, we provide evidence that Activin-type signaling regulates a radial gradient of terminal mitosis within the auditory sensory epithelium, which constitutes a novel mechanism for limiting the number of inner hair cells being produced.

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Staying Current

Essentials of Clinical Informatics ◽

10.1093/med/9780190855574.003.0029 ◽

2019 ◽

pp. 298-304

Author(s):

Karl E. Misulis ◽

Mark E. Frisse

Keyword(s):

Computer Science ◽

Clinical Medicine ◽

Organizational Management ◽

The Body ◽

Clinical Informatics ◽

Payment Methods ◽

Professional Interest ◽

New Findings ◽

Rapid Changes ◽

The Many

Clinical informatics professionals must remain current with rapid changes in technology, expectations, payment methods, organizational management, and regulations. Fundamental principles in medicine, psychology, computer science, informatics, and economics will serve as a vital foundation; the application of these principles through people, organizations, data, processes, and technologies will change with rapidity. Clinical informatics professionals must remain current to understand and implement meaningful next steps as their organizations evolve. This currency can only be obtained through professional engagement with the broader informatics community and through study of new findings and innovations. Like clinical medicine and many other fields, the body of literature in informatics is growing far too rapidly to remain current in every professional interest. To face the challenges ahead, informatics professionals must employ a range of technologies and resources to collaborate and learn across the many applicable disciplines.

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Double sperm cloning (DSC) is a promising strategy in mammalian genetic engineering and stem cell research

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01907-0 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Zhi-ping Zhang ◽

Jun-tao Zhang ◽

Shu-cheng Huang ◽

Xiu-yuan He ◽

Li-xin Deng

Keyword(s):

Stem Cells ◽

Regenerative Medicine ◽

Epigenetic Modification ◽

Embryonic Stem ◽

Immunological Response ◽

Epigenetic Memory ◽

Donor Cells ◽

Induced Pluripotent ◽

The Many ◽

Artificial Activation

Abstract Embryonic stem cells (ESCs) derived from somatic cell nuclear transfer (SCNT) and induced pluripotent stem cells (iPSCs) are promising tools for meeting the personalized requirements of regenerative medicine. However, some obstacles need to be overcome before clinical trials can be undertaken. First, donor cells vary, and the reprogramming procedures are diverse, so standardization is a great obstacle regarding SCNT and iPSCs. Second, somatic cells derived from a patient may carry mitochondrial DNA mutations and exhibit telomere instability with aging or disease, and SCNT-ESCs and iPSCs retain the epigenetic memory or epigenetic modification errors. Third, reprogramming efficiency has remained low. Therefore, in addition to improving their success rate, other alternatives for producing ESCs should be explored. Producing androgenetic diploid embryos could be an outstanding strategy; androgenic diploid embryos are produced through double sperm cloning (DSC), in which two capacitated sperms (XY or XX, sorted by flow cytometer) are injected into a denucleated oocyte by intracytoplasmic sperm injection (ICSI) to reconstruct embryo and derive DSC-ESCs. This process could avoid some potential issues, such as mitochondrial interference, telomere shortening, and somatic epigenetic memory, all of which accompany somatic donor cells. Oocytes are naturally activated by sperm, which is unlike the artificial activation that occurs in SCNT. The procedure is simple and practical and can be easily standardized. In addition, DSC-ESCs can overcome ethical concerns and resolve immunological response matching with sperm providers. Certainly, some challenges must be faced regarding imprinted genes, epigenetics, X chromosome inactivation, and dosage compensation. In mice, DSC-ESCs have been produced and have shown excellent differentiation ability. Therefore, the many advantages of DSC make the study of this process worthwhile for regenerative medicine and animal breeding.

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Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

Nanomaterials ◽

10.3390/nano10020226 ◽

2020 ◽

Vol 10 (2) ◽

pp. 226 ◽

Cited By ~ 4

Author(s):

Tero A.H. Järvinen ◽

Toini Pemmari

Keyword(s):

Regenerative Medicine ◽

Blood Vessels ◽

Recombinant Proteins ◽

Clinical Medicine ◽

Vascular System ◽

Therapeutic Potential ◽

Systemic Administration ◽

Molecular Signature ◽

Postal Code ◽

Organ Specific

Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic blood vessels in the regenerating tissues have a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an appealing opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives to a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine.

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Nanodiamonds: The intersection of nanotechnology, drug development, and personalized medicine

Science Advances ◽

10.1126/sciadv.1500439 ◽

2015 ◽

Vol 1 (7) ◽

pp. e1500439 ◽

Cited By ~ 104

Author(s):

Dean Ho ◽

Chung-Huei Katherine Wang ◽

Edward Kai-Hua Chow

Keyword(s):

Personalized Medicine ◽

Drug Development ◽

Cancer Treatment ◽

Nucleic Acid Delivery ◽

Development Platform ◽

Single Compound ◽

The Many ◽

Preclinical And Clinical Studies ◽

And Personalized Medicine ◽

Unique Chemical

The implementation of nanomedicine in cellular, preclinical, and clinical studies has led to exciting advances ranging from fundamental to translational, particularly in the field of cancer. Many of the current barriers in cancer treatment are being successfully addressed using nanotechnology-modified compounds. These barriers include drug resistance leading to suboptimal intratumoral retention, poor circulation times resulting in decreased efficacy, and off-target toxicity, among others. The first clinical nanomedicine advances to overcome these issues were based on monotherapy, where small-molecule and nucleic acid delivery demonstrated substantial improvements over unmodified drug administration. Recent preclinical studies have shown that combination nanotherapies, composed of either multiple classes of nanomaterials or a single nanoplatform functionalized with several therapeutic agents, can image and treat tumors with improved efficacy over single-compound delivery. Among the many promising nanomaterials that are being developed, nanodiamonds have received increasing attention because of the unique chemical-mechanical properties on their faceted surfaces. More recently, nanodiamond-based drug delivery has been included in the rational and systematic design of optimal therapeutic combinations using an implicitly de-risked drug development platform technology, termed Phenotypic Personalized Medicine–Drug Development (PPM-DD). The application of PPM-DD to rapidly identify globally optimized drug combinations successfully addressed a pervasive challenge confronting all aspects of drug development, both nano and non-nano. This review will examine various nanomaterials and the use of PPM-DD to optimize the efficacy and safety of current and future cancer treatment. How this platform can accelerate combinatorial nanomedicine and the broader pharmaceutical industry toward unprecedented clinical impact will also be discussed.

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History of regenerative medicine in the field of orthopedics

10.25259/jassm_12_2020 ◽

2020 ◽

Vol 1 ◽

pp. 154-158

Author(s):

Abhishek Vaish ◽

William Murrell ◽

Raju Vaishya

Keyword(s):

Regenerative Medicine ◽

Delayed Union ◽

The Body ◽

Cartilage Defects ◽

Cell Therapies ◽

Non Union ◽

Tissue Healing ◽

History Of ◽

Necrosis Of Femoral Head ◽

Natural Tissue

The demand and surge of regenerative medical treatments for various musculoskeletal disorders and injuries have increased exponentially in the recent past. We have reviewed the evolution of these treatments, from the past to the present times. This era has seen a paradigm shift from the replacement to regenerative methods of treatment for many orthopedic disorders. The regenerative medicine helps in restoring the natural tissue in the body at the diseased area. From the ancient methods of provoking tissue healing by noxious stimuli, now, many sophisticated and scientifically proven techniques of regeneration of tissues have come up and are being used globally. Cell therapies have been used as a treatment for a variety of musculoskeletal pathologies including osteoarthritis, cartilage defects, tendinopathies, delayed union and non-unions, non-union of fractures, and treatment of avascular necrosis of femoral head and other bones. Cellular therapies, with or without tissue engineering, seem to the future of regenerative medicine and these may make the replacement of a diseased joint or bone redundant in the near future.

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