Use of Human Cadaveric Mesenchymal Stem Cells for Cell Therapy of a Chronic Radiation-Induced Skin Lesion: A Case Report.

Acute and late radiation-induced injury on skin and subcutaneous tissues are associated with substantial morbidity in radiation therapy, interventional procedures and also are of concern in the context of nuclear or radiological accidents. Pathogenesis is initiated by depletion of acutely responding epithelial tissues and damage to vascular endothelial microvessels. Efforts for medical management of severe radiation-induced lesions have been made. Nevertheless, the development of strategies to promote wound healing, including stem cell therapy, is required. From 1997 to 2014, over 248 patients were referred to the Radiopathology Committee of Hospital de Quemados del Gobierno de la Ciudad de Buenos Aires (Burns Hospital) for the diagnosis and therapy of radiation-induced localized lesions. As part of the strategies for the management of severe cases, there is an ongoing research and development protocol on 'Translational Clinical Trial phases I/II to evaluate the safety and efficacy of adult mesenchymal stem cells from bone marrow for the treatment of large burns and radiological lesions'. The object of this work was to describe the actions carried out by the Radiopathology Committee of the Burns Hospital in a chronic case with more than 30 years of evolution without positive response to conventional treatments. The approach involved the evaluation of the tissular compromise of the lesion, the prognosis and the personalized treatment, including regenerative therapy.

La curación de las heridas de gran superficie y la medicina regenerativa / Wound healing of large surface and regenerative medicine

La medicina regenerativa, con los conocimientos de la biología celular y molecular, llegó a las especialidades quirúrgicas y así a la atención del paciente. Se describen los fundamentos teóricos de un nuevo concepto de curación de las superficies cruentas. Se explica un nuevo procedimiento de curación de las heridas no infectadas a través del uso de un epitelio transitorio que al evitar la evaporación protege a las señales electromagnéticas de información entre célula y célula, así como la regeneración de un nuevo tejido mediante el uso de ADM. Se presentan cinco pacientes críticos, cuatro de ellos con indicación de amputación por la gravedad del traumatismo.

Regenerative medicine with knowledge of cell and molecular biology, reached the surgical specialities and thereby patient care. It describes the theoretical basis of a new concept of wound healing and a new procedure for healing of uninfected wounds through the use of a transitional epithelium to prevent evaporation that protects information of the electromagnetic signals between the cells, and regeneration of a new tissue using ADM. We present five critical patients, four of them with an indication of amputation due to the severity of the injury.

La curación de las heridas de gran superficie y la medicina regenerativa / Wound healing of large surface and regenerative medicine

La medicina regenerativa, con los conocimientos de la biología celular y molecular, llegó a las especialidades quirúrgicas y así a la atención del paciente. Se describen los fundamentos teóricos de un nuevo concepto de curación de las superficies cruentas. Se explica un nuevo procedimiento de curación de las heridas no infectadas a través del uso de un epitelio transitorio que al evitar la evaporación protege a las señales electromagnéticas de información entre célula y célula, así como la regeneración de un nuevo tejido mediante el uso de ADM. Se presentan cinco pacientes críticos, cuatro de ellos con indicación de amputación por la gravedad del traumatismo. (AU)

Regenerative medicine with knowledge of cell and molecular biology, reached the surgical specialities and thereby patient care. It describes the theoretical basis of a new concept of wound healing and a new procedure for healing of uninfected wounds through the use of a transitional epithelium to prevent evaporation that protects information of the electromagnetic signals between the cells, and regeneration of a new tissue using ADM. We present five critical patients, four of them with an indication of amputation due to the severity of the injury. (AU)

Outstanding survival and regeneration process by the use of intelligent acellular dermal matrices and mesenchymal stem cells in a burn pig model.

A pig model with a deep large burn was used to study the regeneration process induced by mesenchymal stem cells (MSCs) and acellular pig dermal matrices, made intelligent by the combination with biodegradable nanofibers loaded with growth factors (granulocyte-macrophage colony-stimulating factor and epidermal growth factor) and coated with the anti-CD44 monoclonal antibody (intelligent acellular dermal matrices, IADMs). These IADMs are specially designed to integrate in the wound bed as new biological scaffolds as well as to specifically recruit and attach circulating and/or externally applied MSCs through the anti-CD44 antibody while delivering precise amounts of growth factors. In this way, the reparative process as well as the aesthetic and functional results were enhanced in our burn model. The animal survived, the wound was completely closed, and total regeneration of the skin was obtained without much scarring. Surprisingly, hair follicles and other skin appendages developed despite the severity and deepness of the burn. Even burned muscles and ribs seemed to have undergone a regenerative process by the end of the study. Based on these findings, we have proposed the use of IADMs and autologous, allogeneic or xenogeneic MSCs, as a new paradigm for the future treatment of large burns and probably other dermatological and cosmetic human conditions.

The next generation of burns treatment: intelligent films and matrix, controlled enzymatic debridement, and adult stem cells.

We describe a novel technology based on nanoengineered multifunctional acellular biologic scaffolds combined with wound dressings and films of the same kind. This method allows selective delivery and release of shielded biomaterials and bioactive substances to a desired wound or damaged tissue while stimulating the selective anchoring and adhesion of endogenous circulating repairing cells, such as mesenchymal stem cells, to obtain a faster and more physiologic healing process. We also present a new controlled enzymatic debridement process for more effective burned tissue scarolysis. In light of our preliminary in vitro and in vivo data, we are convinced that these approaches can include the use of other kinds of adult stem cells, such as endometrial regenerative cells, to improve the vascularization of the constructs, with great potential in the entire tissue and organ regeneration field but especially for the treatment of severely burned patients, changing the way these lesions may be treated in the future.

Dermis acelular porcina (sus scrofa) cargada con antioxidantes de larrea divaricata / Porcine (sus scrofa) acellular dermis load with antioxidants from larrea divaricata

Con el objeto de cargar con antioxidantes de Larrea divaricata una dermis acelular porcina para propósitos terapéuticos, se determinó el contenido de polifenoles y antocianinas de extractos puros, aislados y absorbidos en una dermis acelular porcina. Los valores para polifenoles totales y antocianinas fueron: a) Larrea divaricata: 58,77 + 1,55 mg ácido gálico / 100 g peso fresco, 400,00 + 9,55 mg cianidina 3-glucósido / 100 g peso fresco, repectivamente, b) dermis acelular porcina: 8,86 + 0,55 mg ac. gállico / 100 g peso fresco y 0,10+ 0,00 mg cianidina 3-glucósido / 100 g peso fresco; respectivamente, c) Larrea divaricata absorbida en dermis acelular porcina 45,92 + 0,90 mg ácido gálico / 100 g peso fresco y 155,92 + 5,90 mg cianidina 3-glucósido / 100 g peso fresco, respectivamente. Nosotros concluimos que es posible tener una dermis acelular porcina cargada con antioxidantes de Larrea divaricata para propósitos médicos.

The aim of the study was to evaluate loading with antioxidants from Larrea divaricata a porcine acellular dermis for therapeutic purposes, poliphenols and anthocianins of pure extracts, isolated and absorbed in pig acellular dermis was evaluated. The following values (total polyphenols and anthocianins) were obtained: a) Larrea divaricata: 58,77 + 1,55 mg gallic acid / 100 g fresh weight; 400,95 + 9,55 mg cianydin 3- glucosyde / 100 g fresh weight; respectively; b) porcine acellular dermis: 8,86 + 0,55 mg gallic acid / 100 g fresh weight and 0,10+ 0,00 mg cianydin 3-glucosyde / 100 g fresh weight; respectively, c) L. divaricata absorbed in porcine acellular dermis: 45,92 + 0,90 mg gallic acid / 100 g fresh weight and 155,92 + 5,90 mg cianydin 3-glucosyde / 100 g fresh weight, respectively. We concluded that it is possible to get a porcine acellular dermis loaded with antioxidants from Larrea divaricata for medical purposes.

Matrix superhighways configurations: new concepts for complex organ regeneration.

New ideas and experimental models for tissue and organ regeneration are urgently needed. There are several exciting challenges in the field of organogenesis that need to be defined. The integrated signals and molecular repertoires that shape the particular architecture of specific organs like the kidney or the liver are not completely understood yet. To develop a new scientific platform to be able to build up complex organs we have established a research program using basically Acellular Xenogeneic Isomorphic Matrices (AXIMs) and mesenchymal stem cells (MSCs) generating the necessary concepts for the definition, production, and application of the specific configurations of these matrices for organ regeneration. New and interesting pathways for MSC differentiation were identified. We believe that all extracellular matrices were created fundamentally equal or at least very similar in nature. We also believe that there are true "matrix superhighway configurations" with different three-dimensional geometrical architectures as well as biochemical, electrical, and molecular properties that are tissue and organ specific that influence cell differentiation and organogenesis and will be fundamental for the in vitro regeneration of complex organs for transplantation.

Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: new evidence for their use in regenerative medicine.

OBJECTIVES: Recent work has shown that human bone marrow contains mesenchymal stem cells (MSCs). However, little is known about their presence in peripheral blood. Since these cells are potentially responsible for tissue repair after injury, their number should be increased during these situations. To demonstrate their number during these situations, we measured MSCs in the peripheral blood of healthy donors and burn patients. MATERIALS AND METHODS: Blood samples were obtained from 15 acute burn patients and 15 healthy donors. We performed flow cytometric analysis, using a large monoclonal antibody panel: CD44, CD45, CD14, DR, CD34, CD19, CD13, CD29, CD105, CD1a, CD90, CD38, CD25. MSC phenotype was considered positive for CD44, CD13, CD29, CD90, and CD105, and negative for the other monoclonals. The testing was performed on day 3 after injury. We correlated the results with the age, sex, and size and type of burns. RESULTS: Cells expressing the MSC phenotype were detected in the peripheral blood of both groups. Noteworthy, compared with samples from healthy donors (0.0078 +/- 0.0044), blood obtained from burn patients showed a higher MSC percentage (0.1643 +/- 0.115; P < .001). The percentage of MSCs correlated with the size and severity of the burn. Increased values were also observed among younger patients. CONCLUSIONS: MSCs have an important role in regenerative processes of human tissues. We found cells phenotypically identical to MSCs circulating in physiological number in normal subjects, but in significantly higher amounts during acute large burns. Therefore, they may represent a previously unrecognized circulatory component to the process of skin regeneration.

Human mesenchymal stem cells are tolerized by mice and improve skin and spinal cord injuries.

INTRODUCTION: We sought to use human mesenchymal stem cells (HMSC) for skin and spinal cord repair in mice. MATERIALS AND METHODS: Human bone marrow obtained from a young healthy donor was used to separate and culture human mesenchymal stem cells (HMSC). Ten mice were included in each of four groups. A full-thickness skin defect was surgically performed on all mice in groups 1 and 2. A transverse complete medullar section was performed in groups 3 and 4. Groups 1 and 3 received HMSC IV infusion and local HMSC polymer implant. Groups 2 and 4 received only the IV HMSC infusion. Five control animals from each group went through the same lesions but they didn't receive treatment. RESULTS: After local administration of HMSC into the fibrin polymer combined with the IV infusion of HMSC, there was no immune rejection; all skin defects healed without scar or retraction at a median time of 14 days. Sixty percent of the animals treated with IV infusion and polymer with HMSC simultaneously had improved neurological activities, while all control mice with spinal cord injury experiments died or perpetuated their paralysis with worsening muscular atrophy and increasing propensity to skin damage. CONCLUSIONS: HMSC are not immunologically reactive and can trespass species defense barriers. Animals treated with these cells repaired injuries better than controls. In this way we propose that universal HMSC from donors can be cultured, expanded, and cryopreserved to be used in human organ or tissue regeneration.