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Clinical Trends in Regenerative Medicine

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 47769

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Dr. Dominik Duscher

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Experimental Plastic Surgery, Department of Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
Interests: plastic surgery; regenerative medicine; stem cells; tissue engineering; biomaterials; clinical translation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

What was once considered impossible in medicine is finally becoming possible—tissue regeneration in the treatment of many diseases and conditions. The goal of regenerative medicine is to untangle the language of cells and to develop new treatments to be able to restore or establish normal function by replacing, engineering, or regenerating human cells, tissues, or organs that have been lost or injured due to age, disease, or congenital defects. Regenerative medicine propagates gentle and minimally invasive interventions that are used in both acute injuries and chronic inflammatory conditions. It involves research in multiple areas, each of which is complex, but together, they stand as a powerful combination of technologies, such as stem cells, gene editing, nuclear transfer, proteomics, pharmacology, nanotechnology, tissue engineering, three-dimensional printing, and biomanufacturing. The research in all these fields and disciplines advances rapidly. Therefore, it is crucial to keep up with emerging trends and critical turnarounds in the development of collective knowledge. With this special issue, we hope to encourage submissions that discuss the current state-of-art, address the developing approaches and focus on the current strategies to pursue the objectives of regenerative medicine.

Dr. Dominik Duscher
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Regenerative medicine
Tissue engineering
Stem cells
Clinical translation
Biomaterials

Published Papers (12 papers)

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Research

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14 pages, 5919 KiB

Open AccessArticle

Epidermal-Derived Hedgehog Signaling Drives Mesenchymal Proliferation during Digit Tip Regeneration

by Zeshaan N. Maan, Yuval Rinkevich, Janos Barrera, Kellen Chen, Dominic Henn, Deshka Foster, Clark Andrew Bonham, Jagannath Padmanabhan, Dharshan Sivaraj, Dominik Duscher, Michael Hu, Kelley Yan, Michael Januszyk, Michael T. Longaker, Irving L. Weissman and Geoffrey C. Gurtner

J. Clin. Med. 2021, 10(18), 4261; https://doi.org/10.3390/jcm10184261 - 20 Sep 2021

Cited by 1 | Viewed by 2861

Abstract

Hand injuries often result in significant functional impairments and are rarely completely restored. The spontaneous regeneration of injured appendages, which occurs in salamanders and newts, for example, has been reported in human fingertips after distal amputation, but this type of regeneration is rare in mammals and is incompletely understood. Here, we study fingertip regeneration by amputating murine digit tips, either distally to initiate regeneration, or proximally, causing fibrosis. Using an unbiased microarray analysis, we found that digit tip regeneration is significantly associated with hair follicle differentiation, Wnt, and sonic hedgehog (SHH) signaling pathways. Viral over-expression and genetic knockouts showed the functional significance of these pathways during regeneration. Using transgenic reporter mice, we demonstrated that, while both canonical Wnt and HH signaling were limited to epidermal tissues, downstream hedgehog signaling (through Gli) occurred in mesenchymal tissues. These findings reveal a mechanism for epidermal/mesenchyme interactions, governed by canonical hedgehog signaling, during digit regeneration. Further research into these pathways could lead to improved therapeutic outcomes after hand injuries in humans. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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17 pages, 3884 KiB

Open AccessArticle

Clinical and Radiographic Outcomes of Immature Teeth Treated with Different Treatment Protocols of Regenerative Endodontic Procedures: A Retrospective Cohort Study

by Radovan Žižka, Šimon Belák, Jiří Šedý, Kamila Fačevicová, Iva Voborná and David Marinčák

J. Clin. Med. 2021, 10(8), 1600; https://doi.org/10.3390/jcm10081600 - 09 Apr 2021

Cited by 7 | Viewed by 2768

Abstract

Regenerative endodontic procedure (REP) is a progressive treatment modality for immature permanent teeth with necrotic pulp. The ambiguousness about the predictability of REP outcome in relation to complete disinfection of the root canal system and the occurrence of discoloration still exists. The aim of this retrospective study was to analyze two treatment protocols on clinical success rate, radiographic root development and the occurrence of discoloration. Eighteen patients were treated by a single operator by either treatment protocol according to the American Association of Endodontists (AAEP, n = 9) or a modified protocol (MP, n = 9) with the use of 5% sodium hypochlorite and sandblasting. Patients were followed up after 3, 6, 9, 12, 18 and 24 months and clinical success, radiographic root development and the occurrence of discoloration were assessed. The clinical success of MP was significantly higher in two years follow-up (p = 0.015), but the change in radiographic root area was higher for AAEP (p = 0.017) and the occurrence of discoloration was higher in AAEP (p = 0.029). The use of 5% sodium hypochlorite for a longer period of time leads to a higher success rate. The sandblasting of the access cavity reduces the occurrence of discoloration. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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9 pages, 614 KiB

Open AccessArticle

Autologous Fat Transplantation for Thumb Carpometacarpal Joint Osteoarthritis (Liparthroplasty): A Case Series with Two Years of Follow-UP

by Stefan M. Froschauer, Matthias Holzbauer, Raphael Wenny, Manfred Schmidt, Georg M. Huemer, Oskar Kwasny and Dominik Duscher

J. Clin. Med. 2021, 10(1), 113; https://doi.org/10.3390/jcm10010113 - 31 Dec 2020

Cited by 10 | Viewed by 2518

Abstract

Adipose-derived mesenchymal stem cell (ASC) therapy is currently a focus of regenerative medicine. Lipoaspirate is rich in ASCs and is evolving into a promising, less-invasive tool to treat thumb carpometacarpal osteoarthritis as compared with common surgical techniques, for example, trapeziectomy or prosthesis implantation. The present study aimed to examine the effect of 1 mL intraarticular lipoaspirate injection (liparthroplasty) in 31 thumb carpometacarpal osteoarthritis patients (27 woman and four men) with a median age of 58 (interquartile range (IQR) of 10) years and Eaton–Littler Stage 2 or 3. Median pain levels assessed via visual analogue scale significantly decreased from 7 (IQR 2) to 4 (IQR 6) after six months (p < 0.0001) and 2 (IQR 5) after two years (p < 0.0001). Median pre-interventional Disabilities of the Arm, Shoulder and Hand (DASH) scores of 59 (IQR 26) significantly reduced to a value of 40 (IQR 43) after six months (p = 0.004) and to 35 (IQR 34) after two years (p < 0.0001). Subjective grip strength showed no significant improvement. However, the time until recurrence of symptoms was measured and a cumulative remission rate of 58% was detected after two years. Satisfaction rates were 68% after six months and 51% after two years. In conclusion, liparthroplasty represents a promising option to reduce pain and functional impairment and to postpone surgery for a certain period of time. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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11 pages, 4523 KiB

Open AccessArticle

Management of Radial Nerve Lesions after Trauma or Iatrogenic Nerve Injury: Autologous Grafts and Neurolysis

by Karl Schwaiger, Selim Abed, Elisabeth Russe, Fabian Koeninger, Julia Wimbauer, Hassan Kholosy, Wolfgang Hitzl and Gottfried Wechselberger

J. Clin. Med. 2020, 9(12), 3823; https://doi.org/10.3390/jcm9123823 - 26 Nov 2020

Cited by 5 | Viewed by 3204

Abstract

Background: Proximal radial nerve lesions located between the brachial plexus and its division into the superficial and deep branches are rare but severe injuries. The majority of these lesions occur in association with humerus fractures, directly during trauma or later during osteosynthesis for fracture treatment. Diagnostics and surgical interventions are often delayed. The best type of surgical treatment and the outcome to be expected often is uncertain. Methods: Twelve patients with proximal radial nerve lesions due to trauma or prior surgery were included in this study and underwent neurolysis (n = 6) and sural nerve graft interposition (n = 6). Retrospective analysis of the collected patient data was performed and the postoperative course was systematically evaluated. The Disabilities of the Arm, Shoulder, and Hand (DASH) and the LSUHS (Louisiana State University Health Sciences) scores were used to determine regeneration after surgery. Comparison between the patients’ and calculated normative DASH scores was performed. Results: All patients had a traumatically or iatrogenically induced proximal radial nerve lesion and underwent secondary treatments. The average time from radial nerve lesion occurrence to surgical intervention was approximately four months (1.5–10 months). Eight patients (66.67%) had a humeral fracture. During follow up, no statistically significant difference between the calculated normative and the patients’ DASH scores was observed. The LSUHS scores were at least satisfactory. Conclusions: Neurolysis or sural nerve graft interposition performed within a specific period of time are the primary treatment options for radial nerve lesions. They should be performed depending on the lesion type. Regeneration to a satisfactory degree was observed in all patients, and the majority achieved full recovery of sensory and motor functions. This was the first study to highlight the efficiency of neurolysis and sural nerve graft interposition as secondary treatment interventions, especially for radial nerve lesions. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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11 pages, 594 KiB

Open AccessArticle

Occult Pathologic Findings in Reduction Mammaplasty in 5781 Patients—An International Multicenter Study

by Britta Kuehlmann, Florian D. Vogl, Tomas Kempny, Gabriel Djedovic, Georg M. Huemer, Philipp Hüttinger, Ines E. Tinhofer, Nina Hüttinger, Lars Steinstraesser, Stefan Riml, Matthias Waldner, Clark Andrew Bonham, Thilo L. Schenck, Gottfried Wechselberger, Werner Haslik, Horst Koch, Patrick Mandal, Matthias Rab, Norbert Pallua, Lukas Prantl and Lorenz Larcher Show full author list Hide full author list

J. Clin. Med. 2020, 9(7), 2223; https://doi.org/10.3390/jcm9072223 - 13 Jul 2020

Cited by 5 | Viewed by 2203

Abstract

Breast cancer is among the most commonly diagnosed cancers in the world, affecting one in eight women in their lifetimes. The disease places a substantial burden on healthcare systems in developed countries and often requires surgical correction. In spite of this, much of the breast cancer pathophysiology remains unknown, allowing for the cancer to develop to later stages prior to detection. Many women undergo reduction mammaplasties (RM) to adjust breast size, with over 500,000 operations being performed annually. Tissue samples from such procedures have drawn interest recently, with studies attempting to garner a better understanding of breast cancer’s development. A number of samples have revealed nascent cancer developments that were previously undetected and unexpected. Investigating these so-called “occult” findings of cancer in otherwise healthy patients may provide further insight regarding risk factors and countermeasures. Here, we detail occult findings of cancer in reduction mammaplasty samples provided from a cohort of over 5000 patients from 16 different institutions in Europe. Although the majority of our resected breast tissue specimens were benign, our findings indicate that there is a continued need for histopathological examination. As a result, our study suggests that preoperative imaging should be routinely performed in patients scheduled for RM, especially those with risk factors of breast cancer, to identify and enable a primary oncologic approach. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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12 pages, 4291 KiB

Open AccessArticle

Enhanced Resorption of Liposomal Packed Vitamin C Monitored by Ultrasound

by Lukas Prantl, Andreas Eigenberger, Sebastian Gehmert, Silke Haerteis, Thiha Aung, Reinhard Rachel, Ernst Michael Jung and Oliver Felthaus

J. Clin. Med. 2020, 9(6), 1616; https://doi.org/10.3390/jcm9061616 - 26 May 2020

Cited by 10 | Viewed by 4265

Abstract

Vitamin C is an essential nutrient for humans and is involved in a plethora of health-related functions. Several studies have shown a connection between vitamin C intake and an improved resistance to infections that involves the immune system. However, the body cannot store vitamin C and both the elevated oral intake, and the intravenous application have certain disadvantages. In this study, we wanted to show a new formulation for the liposomal packaging of vitamin C. Using freeze etching electron microscopy, we show the formed liposomes. With a novel approach of post-processing procedures of real-time sonography that combines enhancement effects by contrast-like ultrasound with a transducer, we wanted to demonstrate the elevated intestinal vitamin C resorption on four participants. With the method presented in this study, it is possible to make use of the liposomal packaging of vitamin C with simple household materials and equipment for intake elevation. For the first time, we show the enhanced resorption of ingested liposomes using microbubble enhanced ultrasound imaging. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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10 pages, 738 KiB

Open AccessArticle

Incidence of Anaplastic Large Cell Lymphoma and Breast-Implant-Associated Lymphoma—An Analysis of a Certified Tumor Registry over 17 Years

by Lukas Prantl, Michael Gerken, Florian Zeman, Michael Leitzmann, Michael Koller, Monika Klinkhammer-Schalke, Matthias Evert, Britta Kuehlmann and Niklas Biermann

J. Clin. Med. 2020, 9(5), 1247; https://doi.org/10.3390/jcm9051247 - 25 Apr 2020

Cited by 5 | Viewed by 2520

Abstract

Background: Breast-implant-associated anaplastic large cell lymphoma (BI-ALCL) and primary breast ALCL are rare extranodal manifestations of non-Hodgkin lymphoma. The rarity of both diseases, along with unreleased sales data on breast implants and constant updates of classification systems impede the calculation of an exact incidence. Methods: The database of the Tumor Center Regensburg in Bavaria was searched for patients with CD30-positive and ALK-negative anaplastic large cell lymphoma between 2002 and 2018. These lymphomas were identified by the ICD-O-3 morphology code “97023” and were cross-checked by searching the diagnosis by name the and ICD-10 code C84.7. Furthermore, we tried to calculate the incidence rates and corresponding 95% confidence intervals, standardized to 1,000,000 implant years of breast-implant-associated anaplastic large cell lymphoma and primary breast anaplastic large cell lymphoma. Results: Twelve ALK-negative and CD30-positive anaplastic large cell lymphomas were identified out of 170,405 malignancies. No case was found within the breast tissue and none of the patients had a previous history of breast implant placement. In five cases, lymph node involvement in close proximity to the breast was observed. Conclusion: We found a low incidence of anaplastic large cell lymphoma and no association to breast implants in these patients. A review of the current literature revealed inconsistent use of classification systems for anaplastic large cell lymphomas and potential overestimation of cases. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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13 pages, 2638 KiB

Open AccessArticle

Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5

by Elizabeth Brett, Matthias Sauter, Éadaoin Timmins, Omid Azimzadeh, Michael Rosemann, Juliane Merl-Pham, Stefanie M. Hauck, Peter J. Nelson, Karl Friedrich Becker, Ilse Schunn, Aoife Lowery, Michael J. Kerin, Michael Atkinson, Achim Krüger, Hans-Günther Machens and Dominik Duscher

J. Clin. Med. 2020, 9(4), 991; https://doi.org/10.3390/jcm9040991 - 02 Apr 2020

Cited by 13 | Viewed by 3429

Abstract

The triple-negative breast tumor boundary is made of aligned, linear collagen. The pro-oncogenic impact of linear collagen is well established; however, its mechanism of formation is unknown. An in vitro analogue of the tumor border is created by a co-culture of MDA-MB-231 cells, adipose derived stem cells, and dermal fibroblasts. Decellularization of this co-culture after seven days reveals an extracellular matrix that is linear in fashion, high in pro-oncogenic collagen type VI, and able to promote invasion of reseeded cells. Further investigation revealed linear collagen VI is produced by fibroblasts in response to a paracrine co-culture of adipose derived stem cells and MDA-MB-231, which together secrete high levels of the chemokine CCL5. The addition of monoclonal antibody against CCL5 to the co-culture results in an unorganized matrix with dramatically decreased collagen VI. Importantly, reseeded cells do not exhibit pro-oncogenic behavior. These data illustrate a cellular mechanism, which creates linear extracellular matrix (ECM) in vitro, and highlight a potential role of CCL5 for building striated tumor collagen in vivo. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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Review

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24 pages, 678 KiB

Open AccessReview

Local Treatment of Burns with Cell-Based Therapies Tested in Clinical Studies

by Anna Paulina Domaszewska-Szostek, Marta Olga Krzyżanowska, Anna Maria Czarnecka and Maria Siemionow

J. Clin. Med. 2021, 10(3), 396; https://doi.org/10.3390/jcm10030396 - 21 Jan 2021

Cited by 12 | Viewed by 3631

Abstract

Effective wound management is an important determinant of the survival and prognosis of patients with severe burns. Thus, novel techniques for timely and full closure of full-thickness burn wounds are urgently needed. The purpose of this review is to present the current state of knowledge on the local treatment of burn wounds (distinguishing radiation injury from other types of burns) with the application of cellular therapies conducted in clinical studies. PubMed search engine and ClinicalTrials.gov were used to analyze the available data. The analysis covered 49 articles, assessing the use of keratinocytes (30), keratinocytes and fibroblasts (6), fibroblasts (2), bone marrow-derived cells (8), and adipose tissue cells (3). Studies on the cell-based products that are commercially available (Epicel^®, Keraheal™, ReCell^®, JACE, Biobrane^®) were also included, with the majority of reports found on autologous and allogeneic keratinocytes. Promising data demonstrate the effectiveness of various cell-based therapies; however, there are still scientific and technical issues that need to be solved before cell therapies become standard of care. Further evidence is required to demonstrate the clinical efficacy and safety of cell-based therapies in burns. In particular, comparative studies with long-term follow-up are critical. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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13 pages, 1100 KiB

Open AccessReview

Stem Cells Regenerating the Craniofacial Skeleton: Current State-Of-The-Art and Future Directions

by Jeremie D. Oliver, Wasila Madhoun, Emily M. Graham, Russell Hendrycks, Maranda Renouard and Michael S. Hu

J. Clin. Med. 2020, 9(10), 3307; https://doi.org/10.3390/jcm9103307 - 15 Oct 2020

Cited by 15 | Viewed by 4601

Abstract

The craniofacial region comprises the most complex and intricate anatomical structures in the human body. As a result of developmental defects, traumatic injury, or neoplastic tissue formation, the functional and aesthetic intricacies of the face and cranium are often disrupted. While reconstructive techniques have long been innovated in this field, there are crucial limitations to the surgical restoration of craniomaxillofacial form and function. Fortunately, the rise of regenerative medicine and surgery has expanded the possibilities for patients affected with hard and soft tissue deficits, allowing for the controlled engineering and regeneration of patient-specific defects. In particular, stem cell therapy has emerged in recent years as an adjuvant treatment for the targeted regeneration of craniomaxillofacial structures. This review outlines the current state of the art in stem cell therapies utilized for the engineered restoration and regeneration of skeletal defects in the craniofacial region. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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14 pages, 1708 KiB

Open AccessReview

Adipose Tissue: A Source of Stem Cells with Potential for Regenerative Therapies for Wound Healing

by Lucy V Trevor, Kirsten Riches-Suman, Ajay L Mahajan and M Julie Thornton

J. Clin. Med. 2020, 9(7), 2161; https://doi.org/10.3390/jcm9072161 - 08 Jul 2020

Cited by 22 | Viewed by 6596

Abstract

Interest in adipose tissue is fast becoming a focus of research after many years of being considered as a simple connective tissue. It is becoming increasingly apparent that adipose tissue contains a number of diverse cell types, including adipose-derived stem cells (ASCs) with the potential to differentiate into a number of cell lineages, and thus has significant potential for developing therapies for regenerative medicine. Currently, there is no gold standard treatment for scars and impaired wound healing continues to be a challenge faced by clinicians worldwide. This review describes the current understanding of the origin, different types, anatomical location, and genetics of adipose tissue before discussing the properties of ASCs and their promising applications for tissue engineering, scarring, and wound healing. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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19 pages, 3243 KiB

Open AccessReview

Mechanotransduction in Wound Healing and Fibrosis

by Britta Kuehlmann, Clark A. Bonham, Isabel Zucal, Lukas Prantl and Geoffrey C. Gurtner

J. Clin. Med. 2020, 9(5), 1423; https://doi.org/10.3390/jcm9051423 - 11 May 2020

Cited by 64 | Viewed by 7493

Abstract

Skin injury is a common occurrence and mechanical forces are known to significantly impact the biological processes of skin regeneration and wound healing. Immediately following the disruption of the skin, the process of wound healing begins, bringing together numerous cell types to collaborate in several sequential phases. These cells produce a multitude of molecules and initiate multiple signaling pathways that are associated with skin disorders and abnormal wound healing, including hypertrophic scars, keloids, and chronic wounds. Studies have shown that mechanical forces can alter the microenvironment of a healing wound, causing changes in cellular function, motility, and signaling. A better understanding of the mechanobiology of cells in the skin is essential in the development of efficacious therapeutics to reduce skin disorders, normalize abnormal wound healing, and minimize scar formation. Full article

(This article belongs to the Special Issue Clinical Trends in Regenerative Medicine)

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