Update review on five top clinical applications of human amniotic membrane in regenerative medicine.

Due to the increasing number of studies performed in the field of regenerative medicine during the last two decades, more analytic studies are still needed to clarify the future prospect of this area of science. The main aim of this research was to review the clinical applications of human Amniotic membrane in the field of regenerative medicine critically. Furthermore, in the light of increasing numbers of available products derived from amniotic membrane, we aimed look in depth to see whether regenerative medicine research strategies have a place in the clinical setting. More specifically, in the present study, we attempted to provide insight on developing the new indication for more research and in the next step, for market leaders companies to expand cost-effectiveness of new derived AM products. 20 companies or distributers have offered some commercial products in this field. Survey on more than 90 clinical trials in last five years showed dermatology (and more specific wound healing), orthopedic, and ophthalmology are heavily biased toward multibillion dollar industry. Moreover, urology and dentistry with fewer numbers of clinical data in comparison with the above-mentioned areas, currently are in the path of translation (especially dentistry). In addition, otolaryngology and oncology with the lowest number showed more potential of research thorough understanding the properties that will help guiding the use of AM-derived products in these two areas in future. More than 50% of clinical studies were done or are developing in USA, which have the biggest share in market products. Subsequently, China, Egypt, India, Iran, and Germany with the ongoing clinical trials in different phases may have more approved products in near future.

Robot-assisted orthotopic and heterotopic ovarian tissue transplantation techniques: surgical advances since our first success in 2000.

OBJECTIVE: To demonstrate the technical advances since the time we reported the first successful case in 2000 and our modern approach to autologous transplantation of frozen-thawed human ovarian tissue. DESIGN: A step-by-step video demonstration of three surgical approaches was created by editing the surgical footage obtained during ovarian transplantation procedures. SETTING: Academic. PATIENT(S): Three patients who previously underwent ovarian tissue harvesting and cryopreservation before gonadotoxic cancer treatments or radical cancer surgery are presented. INTERVENTION(S): The illustrated techniques include robot-assisted orthotopic (technique 1) and heterotopic (technique 2) approaches using the da Vinci Xi (Intuitive Surgical) robotic system and a decellularized human extracellular tissue matrix (Alloderm; LifeCell Corp.) as a tissue scaffold, as well as a percutaneous autotransplantation approach (technique 3). MAIN OUTCOME MEASURE(S): Successful completion of procedures without complications and ovarian graft function with demonstration of E2 production and follicle development. RESULT(S): All cases were completed without complications. Ovarian graft function was confirmed by E2 production, follicle growth by 10-14 weeks after transplantation, and later embryo development. CONCLUSION(S): Since our first report of successful restoration of ovarian function after orthotopic transplantation of frozen-banked ovarian tissue in 2000 (1), followed by our first reports of subcutaneous heterotopic transplantation techniques (2, 3), ovarian tissue cryopreservation followed by subsequent transplantation has become a promising fertility preservation option for young women with cancer who do not have sufficient time to undergo oocyte or embryo cryopreservation and for prepubertal girls (4, 5). The same approach also has the advantage of restoring ovarian endocrine function and fertility without a need for assisted reproduction (6, 7). In the very first successful procedure that we reported in 2000, we used conventional laparoscopy, and the tissues were reconstructed and mounted on a polycellulose scaffold (Surgicel) (1, 7). Since then, we have made significant modifications in our surgical approach with potential improvements in outcomes. Here we illustrate three main techniques of ovarian tissue transplantation resulting in the restoration of ovarian function in all cases. In the first two cases, we illustrated the robot-assisted orthotopic and heterotopic approaches using Alloderm. Robotic ovarian transplantation may increase precision, provide more delicate graft handling, and reduce the time from tissue thawing to transplantation (6, 8). Alloderm is regenerated de-epithelized human cadaver skin, which consists of several extracellular matrix components. It has been safely used in the surgery and dentistry fields for enhancing tissue regeneration and vascularization (9, 10). Furthermore, our earlier laboratory work indicated the critical role of extracellular matrix in primordial follicle growth initiation and preantral follicle growth (11, 12). Prior to our use of Alloderm as part of ovarian transplant procedures, we tested it in human ovarian xenograft models and found Alloderm to incorporate well with ovarian tissue (8). Only after that test did we adopt it for use in ovarian transplants. The utility of the extracellular tissue matrix may thus enhance our ovarian autotransplantation techniques by facilitating ovarian reconstruction and potentially improving neovascularization. In fact, we have seen improved follicle growth and response to ovarian stimulation with the use of Alloderm in our first cases (8). We use heterotopic ovarian transplantation when the pelvis is not suitable for autotransplantation due to past radiation or scarring or when there are other medical contraindications for transplantation in the pelvis. The third technique we illustrated was percutaneous heterotopic ovarian autotransplantation. This is a simple approach that can be used in surgically high-risk patients, as it is done with local anesthesia or IV sedation and without entering abdominal cavity. Additionally, same approach can be utilized when there is heightened concern that the ovarian tissue may harbor a disease that can recur, requiring close surveillance and easier removal of the ovarian graft. While ovarian endocrine function and follicle growth are restored with efficiency using the percutaneous ovarian transplants, our initial experience suggests that oocyte quality may be impaired in SC locations (2, 3, 13). Hence that technique may be more suitable when the only purpose is restoration of ovarian endocrine function. However, we have encountered recurrent live births from spontaneous conceptions following SC ovarian transplants, prompting the question of whether the grafted tissue can augment the function of in situ menopausal ovary (13, 14). While ovarian cryopreservation and transplantation may no longer be considered experimental, there are many exciting questions remaining to be answered on the full potential of this procedure.

New approaches targeting brown adipose tissue transplantation as a therapy in obesity.

Brown adipose tissue (BAT) is raising high expectations as a potential target in the fight against metabolic disorders such as obesity and type 2 diabetes. BAT utilizes fuels such as fatty acids to maintain body temperature by uncoupling mitochondrial electron transport to produce heat instead of ATP. This process is called thermogenesis. BAT was considered to be exclusive to rodents and human neonates. However, in the last decade several studies have demonstrated that BAT is not only present but also active in adult humans and that its activity is reduced in several pathological conditions, such as aging, obesity, and diabetes. Thus, tremendous efforts are being made by the scientific community to enhance either BAT mass or activity. Several activators of thermogenesis have been described, such as natriuretic peptides, bone morphogenic proteins, or fibroblast growth factor 21. Furthermore, recent studies have tested a therapeutic approach to directly increase BAT mass by the implantation of either adipocytes or fat tissue. This approach might have an important future in regenerative medicine and in the fight against metabolic disorders. Here, we review the emerging field of BAT transplantation including the various sources of mesenchymal stem cell isolation in rodents and humans and the described metabolic outcomes of adipocyte cell transplantation and BAT transplantation in obesity.

Future Perspectives of Fat Grafting.

Autologous fat grafting is an exciting part of plastic and reconstructive surgery. Fat serves as a filler and its role in tissue regeneration will likely play a more important role in our specialty. As we learn more about the basic science of fat grafting and the standardized techniques and instruments used for fat grafting, this procedure alone or in conjunction with invasive procedures may be able to replace many operations that we perform currently. Its minimally invasive nature will benefit greatly our cosmetic and reconstructive patients, and may even achieve better clinical outcomes.

The next frontier in composite tissue allotransplantation.

Solid organ transplantations became a clinical option in the 1950s. The hand allograft was the pioneer of composite tissue allotransplantation (CTA), successfully started near the end of the last century despite arguments over the practicality and methods. Since then, CTA such as hand and face has continued to progress from the theoretical to clinical reality. The treatment principles, drug combinations, and mechanisms of the immunosuppression medications on which contemporary transplant surgeries have been based continue to develop as researchers and physicians gain more experience in the CTA field. It could be argued that the ethical issues associated with CTA have prevented evolution of the field rather than surgical or technical skill. This is particularly true for allo-head and body reconstruction (AHBR). How can leaders in the field of CTA develop a model that would satisfy ethical concerns? Bolstered by recent successes in the field, is it time to traverse the next frontier? Can AHBR ever be a feasible option in the clinical setting? The reader will be provided with a brief history of CTA from theory to research to clinical practice. A concise description of AHBR as it pertains to the critical procedure (i.e., surgery design) will also be discussed.

The future of cell transplant therapies: a need for tissue grafting.

Current methodologies of solid organ-derived cell transplant therapies introduce donor cells into hosts through a vascular route, a strategy modeled after hematopoietic therapies. These strategies fail because of inefficient engraftment, poor survival of the cells, and propensity for formation of life-threatening emboli. Transplant success necessitates grafting methods, requiring a mixture of appropriate cell sources embedded into or onto precise mixes of extracellular matrix components and then localized to the diseased or dysfunctional tissue, promoting necessary proliferation, engraftment, and vascularization. Grafting technologies are rapidly translatable to therapeutic uses in patients and provide alternative treatments for regenerative medicine.

Composite tissue allotransplantation: current challenges.

Composite tissue allotransplantation (CTA) in the clinic is taking firm root. Success at hand, face, knee, trachea, and laryngeal transplantation has led to widespread interest and increasing application. Despite this, skepticism is common, particularly in the realm of reconstructive surgeons. The risks of immunosuppression remain a barrier to the advancement of the field, as these are perceived by many to be prohibitive. Significant progress in the field require the development of newer immunosuppressive agents with less toxicity and methods to achieve donor specific tolerance. This review focuses on the current state of CTA-both in the clinic and the laboratory. A thorough understanding of the immunology of CTA will allow the widespread application of this promising field.

Graft selection in cerebral revascularization.

Cerebral revascularization constitutes an important treatment modality in the management of complex aneurysms, carotid occlusion, tumor, and moyamoya disease. Graft selection is a critical step in the planning of revascularization surgery, and depends on an understanding of graft and regional hemodynamics, accessibility, and patency rates. The goal of this review is to highlight some of these properties.

Composite tissue allotransplantation: past, present and future-the history and expanding applications of CTA as a new frontier in transplantation.

Composite tissue allotransplantation (CTA) transplantation is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed in over 40 successful hand transplants, 3 facial reconstructions, and vascularized knee, esophageal, abdominal wall, and tracheal allografts. The toxicity of chronic, nonspecific immunosuppression remains a major limitation to the widespread availability of CTA and is associated with opportunistic infections, nephrotoxicity, end-organ damage, and an increased rate of malignancy. Methods to reduce or eliminate the requirement for immunosuppression would represent a significant step forward in the field. Mixed chimerism induces tolerance to solid organ and tissue allografts, including CTA. This overview focuses on the history and expanding applications of CTA as a new frontier in transplantation, and considers the important hurdles that must be overcome through research to allow widespread clinical application.

Composite tissue allotransplantation for the reconstruction of congenital craniofacial defects.

Facial disfigurement in children with congenital craniofacial defects can lead to decreased self-esteem and poor self-perception. Traditional methods of reconstruction can fail to achieve a normal appearance in patients with severe disfigurements. Composite tissue allotransplantation (CTA) in children could offer a unique reconstructive opportunity. A discussion of the usage of CTA for congenital craniofacial defects is thus warranted. Treatment of severe craniofacial clefts, Treacher-Collins syndrome, hemifacial microsomia, and some vascular anomalies can yield unsatisfactory results, even after multiple surgeries. CTA provides the advantage of intact vascularized bone that would not need to be reshaped to fit the defect, with the correct donor match. CTA also provides reconstruction with similar tissue type in regions of the central midface such as the nose, lips, and eyelids. With advances in transplant immunology to devise mechanisms to decrease immunosuppression and induce donor antigen-specific tolerance, CTA may be a future reality in the pediatric population.

[New strategies for tissue replacement in the head and neck region]. / Neue Strategien zum Gewebeersatz im Kopf-Hals-Bereich.

In recent years there has been an increase in the need for tissue replacement in the head and neck region. The disadvantages of classical reconstructive procedures are donor site morbidity for autologous transplants and the immunogenity of allogenous transplants. Tissue engineering is a promising method for the generation of autologous cartilagenous transplants for plastic and reconstructive surgery for closure of large defects by the use of minimal amounts of material for reconstruction. For this purpose harvested material must be cultivated in suitable culture/carrier systems. One obstacle is the loss of phenotype and function once the cells are detached from their environment (dedifferentiation). Adult mesenchymal stem cells are a valuable cell source for tissue engineering. The underlying strategy of using stem cells is the replacement of functionally compromised cells either by in vitro expanded stem cells or activation of stem cells in the tissue. However, there are still problems regarding valuable markers for cellular differentiation and the controlled differentiation towards a specific phenotype.

[Development and status quo of testis transplantation].

A lot of advances have been made in testis autotransplantation, testis homotransplantation, testicular tissue transplantation, Leydig cell transplantation and spermatogonial stem cell transplantation in the past decades. And recent years, have witnessed remarkable progress in Leydig cell transplantation and spermatogonial stem cell transplantation, which promise to be new means for the treatment of male infertility and hypogonadism. The development and present state of testis transplantation are summarized in this paper based on the related literature of recent years.

Emerging technologies and fourth generation issues in cartilage repair.

The goals of successful cartilage repair include reducing pain, improving symptoms, and long-term function; preventing early osteoarthritis and subsequent total knee replacements; and rebuilding hyaline cartilage instead of fibrous tissue. Current methods such as microfracture, osteoarticular autograft transfer system, mosaicplasty, and autologous chondrocyte implantation are somewhat successful in regenerating cartilage; however, they also have significant limitations. The future of fourth generation cartilage repair focuses on gene therapy, the use of stem cells (bone marrow, adipose, or muscle derived), and tissue engineering. Emerging techniques include creating elastin-like polymers derived from native elastin sequences to serve as biocompatible scaffolds; using hydrogels to obtain a homogeneous distribution of cells within a 3-dimensional matrix; and using nonviral gene delivery via nucleofection to allow mesenchymal stem cells the ability to express osteogenic growth factors. Although many of the techniques mentioned have yet to be used in a cartilage regeneration model, we have tried to anticipate how methods used in other specialties may facilitate improved cartilage repair.

A second-generation autologous chondrocyte implantation approach to the treatment of focal articular cartilage defects.

Autologous chondrocyte implantation (ACI) is the most widely used cell-based surgical procedure for the repair of articular cartilage defects. Challenges to successful ACI outcomes include limitation in defect size and geometry as well as inefficient cell retention. Second-generation ACI procedures have thus focused on developing three-dimensional constructs using native and synthetic biomaterials. Clinically significant and satisfactory results from applying autologous chondrocytes seeded in fibrin within a biodegradable polymeric material were recently reported. In the future, third-generation cell-based articular cartilage repair should focus on the use of chondroprogenitor cells and biofunctionalized biomaterials for more extensive and permanent repair.

Bridging defects: autologous nerve grafts.

Autologous nerve grafting has been performed since 1876 without success. Since the 1960s, the interfascicular nerve grafting technique has provided a reliable method to bridge very long nerve defects with predictable results. Personal experience of over 40 years has demonstrated that donor site morbidity is minimal if certain precautions are observed. Donor site morbidity does not justify the use of alternative techniques. However, in vast defects like brachial plexus lesions, the number of available autografts is insufficient. We do need alternative techniques like tubulisation, however, not to replace autologous nerve grafts but to supplement them.

Twenty years experience with the gastroepiploic artery graft for CABG.

BACKGROUND: To improve the longterm outcome after CABG, several strategies have been used using arterial conduits. Our 20 years experience with the right gastroepiploic artery (GEA) graft was evaluated. METHODS AND RESULTS: In 1352 patients having CABG with the GEA graft, (1092 men, mean 63 years, 99% multivessel disease, and mean EF 0.51), internal thoracic artery, saphenous vein, and radial artery grafts were concomitantly used in 1312 (97%), 783 (58%), and 128 (8%) patients, respectively. The mean number of distal anastomoses was 3.1, and 2.4 coronary arteries were bypassed with arterial grafts. The sites for GEA grafting were 70 anterior descending, 268 circumflex, and 1089 right coronary arteries. The operative mortality was 1.26%. In 1118 follow-up patients (82.6%), 5, 10, and 15 years survival rates were 91.7%, 81.4%, and 71.3%, and the cardiac death-free survival rates were 95.8%, 91.7%, and 88.6%, respectively. The cumulative patency rate of the GEA graft was 97.1% at 1 month, 92.3% at 1 year, 85.5% at 5 years, and 66.5% at 10 years, respectively. In 172 skeletonized GEA grafts with 233 distal anastomoses, the patency rate at immediate, 1, and 4 years after surgery was 97.6%, 92.9%, and 86.4%, respectively. In 124 patients with late (5 to 17 years) restudy, patency rate was 96% (114/119) in the left internal thoracic artery, 87% (108/124) in GEA, and 68% (67/98) in saphenous vein grafts. New stenosis was uncommon in GEA. CONCLUSION: The GEA graft is a safe and effective arterial conduit for CABG.

Transplantation of the hand, face, and composite structures: evolution and current status.

This article reviews the world experience in the newly emerging field of composite tissue allotransplantation. These allografts contain multiple tissues that are usually musculoskeletal structures with a skin or epithelial surface, such as hand, facial structures, larynx, tongue, ear, knee/femur, abdominal wall, and penis. They represent a new transplantation field, with only a 10-year experience and just over 50 clinical cases. This review of the 10-year world experience found uniform technical success, immunologic biology, and immunosuppression regimens very similar to solid organ transplants, and success strongly correlated with adherence to guidelines for psychiatric screening, thorough preparation of patient and families, intense postoperative monitoring, and assurance of medication access. All failures reported have been caused by lapses in these parameters. This early experience shows a great potential for application of these new procedures to the most challenging reconstructive needs.

Stem cells: proyecciones en ingeniería en tejido / Stem cells: tissue engineering projections

Células Madre o Stem Cells se definen como células con capacidad de clonación y auto renovación que se diferencian hacia múltiples linajes celulares. El término de totipotencialidad está reservado para aquellas Células Madre con capacidad ilimitada, que pueden dar origen a todos los tejidos diferenciados del cuerpo humano, junto a la placenta y membranas ovulares. Los términos multipotente y pluripotente son esencialmente sinónimos refiriéndose a la habilidad de diferenciarse hacia múltiples linajes celulares del organismo. Este proceso ha abierto una nueva alternativa terapéutica que se conoce como Ingeniería en Tejido la cual abre paso a la investigación, posibles vías terapéuticas de estudio, tales como la terapia celular, utilización de las células madre en la regeneración de tejido, aprovechando el proceso natural de renovación celular para reparar tejidos dañados o suplir algunos tejidos ausentes.

Equine pericardium for dural grafts: clinical results in 200 patients.

AIM: Serous sheets are currently used in Neurosurgery as dural substitute. The aim of this study is to demonstrate that the horse pericardium, which has the essential charasteristics of reabsorbable membranes and moreover is BSE-free, is an excellent dural substitute. METHODS: 200 patients, 53 suffering from cranial traumatic conditions and 97 from cranial and craniospinal neoplastic pathologies, underwent a surgical procedure with the application of horse pericardium as a dural prosthesis. RESULTS: The follow-up controls of the patients included a neurosurgical visit and advanced diagnostic imaging (CT or MR). In the first 3 cases, an accumulation of CSF occurred under the surgical edge. Lumbar 7-days drainage was required in just one case. The use of Zero 5 suture seems to have obviated this problem, as it was never observed again in subsequent cases. The diagnostic imaging showed no alterated images and no clinical-neurological sequelae regarding the prosthesis in question were recorded. CONCLUSIONS: The Audiomesh Neuro prosthesis has all the characteristics of reabsorbable membranes: they are free from antigenic effects and do not produce any toxic catabolites. The membrane proved to be resistant to surgical suture, impermeable to CSF and is transparent. Yet the suture must be carried out carefully through a small non-traumatic needle. Audiomesh Neuro does not adhere to the underlying cerebral cortex and does not cause any clinical evidence or radiological artifacts.