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.

Nerve graft versus nerve transfer for neonatal brachial plexus: shoulder outcomes.

OBJECTIVE: The decision-making in neonatal brachial plexus palsy (NBPP) treatment continues to have many areas in need of clarification. Graft repair was the gold standard until the introduction of nerve transfer strategies. Currently, there is conflicting evidence regarding outcomes in patients with nerve grafts versus nerve transfers in relation to shoulder function. The objective of this study was to further define the outcomes for reconstruction strategies in NBPP with a specific focus on the shoulder. METHODS: A cohort of patients with NBPP and surgical repairs from a single center were reviewed. Demographic and standard clinical data, including imaging and electrodiagnostics, were gathered from a clinical database. Clinical data from physical therapy evaluations, including active and passive range of motion, were examined. Statistical analysis was performed on the available data. RESULTS: Forty-five patients met the inclusion criteria for this study, 19 with graft repair and 26 with nerve transfers. There were no significant differences in demographics between the two groups. Understandably, there were no patients in the nerve grafting group with preganglionic lesions, resulting in a difference in lesion type between the cohorts. There were no differences in preoperative shoulder function between the cohorts. Both groups reached statistically significant improvements in shoulder flexion and shoulder abduction. The nerve transfer group experienced a significant improvement in shoulder external rotation, from -78° to -28° (p = 0.0001), whereas a significant difference was not reached in the graft group. When compared between groups, there appeared to be a trend favoring nerve transfer in shoulder external rotation, with the graft patients improving by 17° and the transfer patients improving by 49° (p = 0.07). CONCLUSIONS: In NBPP, patients with shoulder weakness experience statistically significant improvements in shoulder flexion and abduction after graft repair or nerve transfer, and patients with nerve transfers additionally experience significant improvement in external rotation. With regard to shoulder external rotation, there appear to be some data supporting the use of nerve transfers.

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.

Intestinal transplant registry report: global activity and trends.

The Registry has gathered information on intestine transplantation (IT) since 1985. During this time, individual centers have reported progress but small case volumes potentially limit the generalizability of this information. The present study was undertaken to examine recent global IT activity. Activity was assessed with descriptive statistics, Kaplan-Meier survival curves and a multiple variable analysis. Eighty-two programs reported 2887 transplants in 2699 patients. Regional practices and outcomes are now similar worldwide. Current actuarial patient survival rates are 76%, 56% and 43% at 1, 5 and 10 years, respectively. Rates of graft loss beyond 1 year have not improved. Grafts that included a colon segment had better function. Waiting at home for IT, the use of induction immune-suppression therapy, inclusion of a liver component and maintenance therapy with rapamycin were associated with better graft survival. Outcomes of IT have modestly improved over the past decade. Case volumes have recently declined. Identifying the root reasons for late graft loss is difficult due to the low case volumes at most centers. The high participation rate in the Registry provides unique opportunities to study these issues.

Fecal microbiota transplantation in treating Clostridium difficile infection.

Clostridium difficile infection (CDI) is an increasingly common and severe international health problem. Customary treatment of this infection, usually with antibiotics, is often ineffective and its recurrence is common. In recent years the treatment of recurrent or refractory CDI by the transfer of stool from an uninfected person, so called fecal "microbiota transplantation" has become recognized as effective and generally safe. The effectiveness of this novel treatment is incompletely defined but is likely to be due to its correction of the intestinal dysbiosis that characterizes the disease. Practical methods for the administration of the transplantation have been described. This review summarizes the current reported experiences with fecal microbiota transplantation in the treatment for CDI.

Therapeutic faecal microbiota transplantation: current status and future developments.

PURPOSE OF REVIEW: Faecal microbiota transplantation (FMT) has undergone dramatic progression over the past year and continues to evolve as knowledge of the gastrointestinal microbiota (GiMb) develops. This review summarizes therapeutic advances in FMT, latest FMT therapies and presents the potential of FMT therapeutics in other gastrointestinal and extra-intestinal conditions. RECENT FINDINGS: The GiMb is now known to have a central role in the pathogenesis of many diseases. The success of FMT in curing Clostridium difficile infection (CDI) is well established and preliminary findings in other gastrointestinal conditions are promising. Published data from over 500 CDI cases suggest that FMT is generally well tolerated with minimal side effects. The commercial potential of FMT is being explored with several products under development, including frozen GiMb extract, which has been shown highly effective in treating relapsing CDI. Such products will likely become more available in coming years and revolutionize the availability and method of delivery of GiMb. SUMMARY: Recent literature unequivocally supports the use of FMT in treating relapsing CDI. Trials are underway to determine the therapeutic potential of FMT in other conditions, particularly inflammatory bowel disease. Therapeutic FMT is a dynamic field with new and emerging indications along with ongoing developments in optimal mode of administration.

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.

Biomaterial design strategies for the treatment of spinal cord injuries.

The highly debilitating nature of spinal cord injuries has provided much inspiration for the design of novel biomaterials that can stimulate cellular regeneration and functional recovery. Many experts agree that the greatest hope for treatment of spinal cord injuries will involve a combinatorial approach that integrates biomaterial scaffolds, cell transplantation, and molecule delivery. This manuscript presents a comprehensive review of biomaterial-scaffold design strategies currently being applied to the development of nerve guidance channels and hydrogels that more effectively stimulate spinal cord tissue regeneration. To enhance the regenerative capacity of these two scaffold types, researchers are focusing on optimizing the mechanical properties, cell-adhesivity, biodegradability, electrical activity, and topography of synthetic and natural materials, and are developing mechanisms to use these scaffolds to deliver cells and biomolecules. Developing scaffolds that address several of these key design parameters will lead to more successful therapies for the regeneration of spinal cord tissue.

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.

Advances in translational transplant immunology.

Recent developments in basic and translational immunology open new exciting perspectives for inducing transplantation tolerance in the clinic. Induction of tolerance, defined as permanent acceptance of the transplant in the absence of continuous immunosuppression, is an achievable goal. However, a number of hurdles still need to be overcome before immunosuppressive drugs can be safely withdrawn in solid organ transplant recipients. Additional strategies for improving long-term outcomes were examined, including best methods for apply using various biomarkers in the clinical setting to improve the diagnosis and management of ongoing renal damage. Detection of a potential or existing immune response to tissue grafts is an important first step in improving the survival of heart, liver, and kidney transplant patients.

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.