Colegio Mexicano de Ortopedia y Traumatología

Colegio Mexicano de Ortopedia y Traumatología
CMO en linea....

lunes, 31 de diciembre de 2012

Double-Row Rotator Cuff Repair | Treatment for Rotator Cuff Tear


Double-Row Rotator Cuff Repair | Treatment for Rotator Cuff Tear

Dr. Peter J. Millett (http://drmillett.com | 970.479-5879), is an orthopedic shoulder surgeon and sports medicine specialist in private practice at the Steadman Clinic in Vail, Colorado. He treats a variety of complex conditions associated with the shoulder joint. 

This educational video discusses the knotless self-reinforcing double-row rotator cuff repair for rotator cuff injuries. A live, internal video is taken during surgery to show the process of how the procedure is performed.

domingo, 30 de diciembre de 2012

Tratamiento adyuvante con fenol en tumores óseos benignos agresivos y malignos de bajo grado en pacientes con esqueleto inmaduro

Acta Ortopédica Mexicana

Vaquerizo V, Abril JC, Ramírez A, Montes E
Tratamiento adyuvante con fenol en tumores óseos benignos agresivos y malignos de bajo grado en pacientes con esqueleto inmaduro
Acta Ortop Mex 2012; 26 (2)
Idioma: Español
Referencias bibliográficas: 32
Paginas: 107-111
Archivo PDF: 78.75 Kb.
RESUMEN
Introducción: El tratamiento quirúrgico de los tumores óseos benignos agresivos se basa en la resección intralesional asociada al uso de un tratamiento adyuvante local que evite la recidiva local. El objetivo de nuestro estudio es valorar la efectividad del tratamiento adyuvante con fenol en tumores óseos benignos, agresivos y malignos de bajo grado en pacientes inmaduros. Material y métodos: Realizamos un estudio retrospectivo descriptivo de 37 pacientes, 13 niñas y 24 niños, con tumores óseos que fueron tratados mediante curetaje y la aplicación de fenol intralesional entre Enero de 1989 y Enero de 2006. El presente estudio incluía 35 tumores benignos grado III según la clasificación de Campanacci y 2 malignos de bajo grado, grado IA según Enneking. Resultados: El seguimiento mínimo fue de 5 años. La tasa local de recidiva fue de 13.5%. La edad media en el momento de la cirugía fue de 10.7 años (DS ± 4.4). El seguimiento medio de los pacientes fue de 104.9 meses (DS ± 41.9). El tiempo medio entre la cirugía y la recidiva fue de 18.8 meses (DS ± 11.81). El 18.9% de los pacientes desarrollaron complicaciones durante el seguimiento. La calificación de la MSTS fue de 28.7 puntos (DS ± 1.7). Discusión: El tratamiento de los tumores óseos mediante la aplicación de fenol presenta una tasa de recidivas baja y un pequeño porcentaje de complicaciones, por lo que está indicado en el manejo de los tumores óseos agresivos localmente.

Palabras clave:fenol, neoplasias óseas, niños.

“XXVII Jornada Nacional de Ortopedia, 58° Reunión anual” México, Acapulco, 2013

                  http://www.smo.edu.mx/jornada2013/


                                   


El Colegio Mexicano de Ortopedia y Traumatología, A.C., tiene el agrado de presentarles su proyecto anual la “XXVII Jornada Nacional de Ortopedia, 58° Reunión anual”, que se llevará a cabo en el bello puerto de Acapulco del 1° al 5 de mayo del 2013.

Nuestra sede, Hotel Acapulco Princess nos proporcionará el cupo y la comodidad que requiere nuestro grupo, con la ventaja de que el hospedaje y las actividades serán en el mismo recinto proporcionando facilidades y seguridad así como innumerables actividades recreativas, sol y playa. Esto constituye el lugar adecuado para compartir con nuestra familia todas las experiencias que estamos planeado para la ortopedia Nacional e Internacional.

Se está preparando un nutrido programa académico, con la participación de profesores nacionales e internacionales de reconocido prestigio, trabajando en conjunto con el profesionalismo de los Titulares de Capítulo de Especialización del Colegio y con el entusiasmo del Comité de Damas se esta organizando un atractivo programa socio-cultural para acompañantes.

Para este evento contaremos con la asistencia de la Federación Europea de Sociedades de Ortopedia y Traumatología (EFORT) quien impartirá cursos instruccionales. Tendremos como sociedad invitada a la Sociedad Española de Ortopedia y Traumatología (SECOT) estamos seguros de que con su entusiasmo y experiencia aportarán gran calidad a nuestras actividades académicas. La unión de la Ortopedia Latinoamericana es una de las metas de nuestro Colegio, es por eso que hemos invitado a Venezuela y Guatemala como países participantes.

Las actividades sociales se están planeando para que otorguen una verdadera convivencia entre nosotros y con innumerables sorpresas que constituirán eventos de primera calidad. Contaremos con la exposición de la industria farmacéutica y de empresas fabricantes y distribuidores de equipo, material e insumos necesarios en el quehacer de nuestra especialidad. Mi mayor interés con ustedes es que esta Jornada les sea de gran provecho profesional y que sean parte del éxito de este gran evento.

Queda pues una invitación abierta a la Ortopedia Nacional a que nos acompañen a este trascendente evento que abrirá sus puertas a todos por igual y espera recibirlos con los brazos abiertos como el inicio de la nueva era de Unidad y Calidad

Cordialmente
Dr. Salvador Oscar Rivero Boschert
Presidente CMO

Lumbar Plexus - Structure and Branches - Anatomy Tutorial


Lumbar Plexus - Structure and Branches - Anatomy Tutorial}

sábado, 29 de diciembre de 2012

Condroblastoma. Caso clínico





















Fractura metafisiaria distal de radio

http://ortocritica.blogspot.mx/2012/03/caso-mensual-i-marzo-fractura.html
Fractura metafisiaria distal de radio



Femenina de 61 años. Afanadora.
Portadora de DMT2 controlada con dieta e hipoglucemiantes orales.


Presenta hace 2 días caída del plano de sustentación al estar laborando y evoluciona posteriormente con dolor, deformidad así como equimosis y crepitaciones en la porción metafisiaria distal de la mano derecha sin datos de exposición ósea, sin lesión vascular y nerviosa por lo que es trasladada a unidad de urgencias para valoración integral donde se toman Rxs Ap y lateral de muñeca y al detectar lesión de tipo fracturaria se realiza reducción de la fractura con colocación de férula. Ante las numerosas dudas que le plantean inicialmente en cuanto a su tratamiento, la paciente pide una segunda y tercera opinión por parte de cirujanos Ortopedistas y finalmente acude con usted planteándole las siguientes interrogantes las cuales deberá de responder usted en un Informe bien expedido y debidamente redactado a su seguro Médico de gastos mayores fundamentado académicamente con artículos con los más altos niveles de evidencia.










1.- ¿Cuál es el diagnóstico integral y: el tratamiento debe de ser conservador con la colocación de un aparato de yeso o mediante un procedimiento quirúrgico y por qué?


2.- Si se optara por un tratamiento conservador; cuánto tiempo tardaría en consolidar la lesión y en cuánto tiempo se reincorporaría a sus actividades laborales de lleno y qué complicaciones potenciales se podrían presentar (en orden de importancia y frecuencia).



3.- Cuál sería la diferencia en cuanto a su función a corto, mediano y largo plazo en caso de que se optara por un tratamiento conservador versus tratamiento quirúrgico con placa o mini-fijadores?



4.- ¿Se le debe de colocar injerto autólogo o de banco de tejidos en el sitio de la lesión en caso de optar por un tratamiento quirúrgico con reducción abierta?



5.- ¿Cuáles serían las diferencias entre el optar por una reducción cerrada y colocación de minifijadores versus utilizar una placa con abordaje posterior en cuanto al tiempo de recuperación funcional, grado de función a mediano y largo plazo, tiempo de consolidación, complicaciones y secuelas y cuál tratamiento es el más indicado para este paciente en particular?

PIPJ injury finger

Ankle Fractures – Causes, Symptoms, and Treatment

http://seattlefootandanklesurgery.com/ankle-fractures-causes-symptoms-and-treatment/


Ankle Fractures – Causes, Symptoms, and Treatment

Ankle injuries are among the most common of the bone injuries. An ankle fracture is also known as a broken ankle. These types of fractures occur when one or more of the ankle joint bones separate into pieces. It is typical for the ankle ligaments to be damaged with an ankle injury. The types of ankle fractures and injury we cover include lateral malleolus fracture, medial malleolus fracture, posterior malleolus fracture, bimalleolar fracture, and trimalleolar fracture.

Anatomy

The ankle consists of three bones that come together:  the tibia (shin bone), the fibula (small lower leg bone), and the talus (a foot bone). The medial malleolus is the inner portion of the tibia. The posterior malleolus is the back portion of the tibia. The lateral malleolus is the end of the fibula. The syndesmosis is the joint between the fibula and tibia, which connects together with ligaments.

Cause

Broken ankles occur in all age groups. They come about when there is twisting or rotating of the ankle during a fall or impact of a car accident. Many refer to this type of injury as a “rolled” ankle.

Symptoms

A severe ankle sprain feels the same as a broken ankle. Common complaints include immediate, severe pain, bruising, tenderness to the touch, swelling, inability to bear weight, and a deformity of the ankle. For severe ankle fractures, the bone may protrude through the skin.

Diagnosis

Because it is difficult to tell a sprain from a fracture, our orthopedic specialists recommend an evaluation by x-ray. Depending upon the type of fracture the surgeon finds, he may order a “stress x-ray” for further evaluation. In some cases, the surgeon orders a computed tomography (CAT scan) or magnetic resonance imaging (MRI) for further evaluation.

Lateral Malleolus Fracture Treatment

A lateral malleolus fracture is a fracture of the fibula bone. Since there are different levels at which the fibula can be injured, the treatment depends on the severity.
Nonsurgical Treatment – When lateral malleolus fractures are not out of place, the surgeon will treat these without surgery. The surgeon places you in a short leg cast or other device for protection. Depending on the injury, you will not be able to put weight on the affected leg for 4 to 6 weeks, meaning you will have to use crutches.
Surgical Treatment – For lateral malleolus fractures that are out of place, the orthopedic specialist will perform surgery on the injury. To make the ankle stable, he uses a plate and screws or screws and a rod. These attach to the bone fragments to realign the fibula so it can heal properly.

Medial Malleolus Fracture Treatment 

A medial malleolus fracture can also involve injury to the fibula, the posterior malleolus, and the ankle ligaments. Just like the lateral types, the orthopedic specialist treats medial malleolus fractures according to their severity.
Nonsurgical Treatment – If the fracture is in alignment, it can be treated without surgery. The doctor put you in a removable brace or short leg cast to be worn for 4 to 6 weeks. The doctor recommends crutches also for a period of time.
Surgical Treatment – The surgeon will perform a procedure if the medial malleolus fracture is unstable and out of alignment. If the injury includes impaction of the ankle joint (damage to the cartilage surfaces), the surgeon will sometimes apply bone graft to repair it and decrease later risk of arthritis development. Many different techniques are used for this type of surgery.

Posterior Malleolus Fracture Treatment

A posterior malleolus fracture is a break in the back of the shinbone near the ankle joint. These types of fractures often include ligament damage. Many times with a posterior malleolus fracture, a lateral malleolus injury occurs.
Nonsurgical Treatment – Like other ankle fractures, fractures that are in alignment can often be treated conservatively without surgery. The orthopedic specialist will place you in a short leg cast or other device and recommend crutches for 4 to 6 weeks.
Surgical Treatment – Surgery is necessary when the bones are not in proper position, and the break is serious. The surgeon can use screws and plates along the back area of the shinbone to hold the bones in place while they heal.

Bimalleolar Fracture Treatment

“Bi” simply means two. When fractures are bimalleolar, this means that two or more parts of the malleoli of the ankle are involved. These injuries typically involve the lateral malleolus and the media malleolus. Bimalleolar fractures are not stable, as they are also often associated with ligament damage. Many times, there is a break of the fibula along with other structure damage.
Nonsurgical Treatment – Bimalleolar fractures require surgery. However, if you have significant health problems, the surgeon will not operate and recommend conservative treatment. The doctor uses a splint or short leg cast to stabilize and protect the injury. Also, you will not be able to bear weight on the ankle for 4 to 6 weeks.
Surgical Treatment – Because of the complexity of these types of fractures, the orthopedic specialist may combine surgical techniques in order to repair the various structures. Often times, a plate and screws are used to align bone fragments. Also, it may be necessary for the surgeon to use bone graft in bimalleolar fractures.

Trimalleolar Fracture Treatment

“Tri” means three. Trimalleolar injuries involve all three malleoli of the ankle. These types of fractures are unstable injuries and dislocation is common.
Nonsurgical Treatment –Unless you are in considerable poor health, the orthopedic specialist will recommend surgery for trimalleolar fractures. However, if you cannot undergo surgery, the surgeon will place your lower leg in a cast or removable device for stabilization and place you on crutches.
Surgical Treatment – These types of fractures are complex and require a combination of surgical efforts for repair. The surgeon will often use plates and screws, bone grafting, and other techniques during the procedure. Because dislocation is common, the doctor will have to properly align the bone and ligaments.
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Current insights on the regenerative potential of the periosteum

http://onlinelibrary.wiley.com/doi/10.1002/jor.22181/full
Current insights on the regenerative potential of the periosteum: Molecular, cellular, and endogenous engineering approaches (pages 1869–1878)
Céline Colnot, Xinping Zhang and Melissa L. Knothe Tate
Article first published online: 9 JUL 2012 | DOI: 10.1002/jor.22181

Keywords:

  • periosteum;
  • regenerative medicine;
  • tissue engineering;
  • bone biology;
  • advanced materials

Abstract

While century old clinical reports document the periosteum's remarkable regenerative capacity, only in the past decade have scientists undertaken mechanistic investigations of its regenerative potential. At a Workshop at the 2012 Annual Meeting of Orthopaedic Research Society, we reviewed the molecular, cellular, and tissue scale approaches to elucidate the mechanisms underlying the periosteum's regenerative potential as well as translational therapies engineering solutions inspired by its remarkable regenerative capacity. The entire population of osteoblasts within periosteum, and at endosteal and trabecular bone surfaces within the bone marrow, derives from the embryonic perichondrium. Periosteal cells contribute more to cartilage and bone formation within the callus during fracture healing than do cells of the bone marrow or endosteum, which do not migrate out of the marrow compartment. Furthermore, a current healing paradigm regards the activation, expansion, and differentiation of periosteal stem/progenitor cells as an essential step in building a template for subsequent neovascularization, bone formation, and remodeling. The periosteum comprises a complex, composite structure, providing a niche for pluripotent cells and a repository for molecular factors that modulate cell behavior. The periosteum's advanced, “smart” material properties change depending on the mechanical, chemical, and biological state of the tissue. Understanding periosteum development, progenitor cell-driven initiation of periosteum's endogenous tissue building capacity, and the complex structure–function relationships of periosteum as an advanced material are important for harnessing and engineering ersatz materials to mimic the periosteum's remarkable regenerative capacity. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1869–1878, 2012
A workshop was held at the 2012 Orthopaedic Research Society Annual Meeting to present the science of the periosteum and its regenerative potential. While clinical reports of the periosteum's remarkable regenerative capacity can be found in century old scientific literature, mechanistic investigations of its regenerative potential have been published mostly in the past decade. The periosteum comprises a complex, composite structure that provides a niche for pluripotent cells and a repository for molecular factors that modulate cell behavior. In addition, periosteum exhibits advanced, smart material properties that change depending on the mechanical, chemical, and biological state of the tissue. Hence, the aim of the workshop was to review molecular, cellular, and tissue scale approaches to elucidate the mechanisms underlying the periosteum's regenerative potential and to discuss these approaches in light of translational therapies and engineering solutions inspired by the its remarkable regenerative capacity. An interactive panel discussion highlighted current hurdles to advancement, clinical translation of these insights, and current controversies in the field.

DEVELOPMENT OF THE PERIOSTEUM AND ITS ROLE DURING BONE REPAIR

The periosteum is a thin tissue lining the outer surface of bone. From a structural perspective, the periosteum is a bilayered membrane. The outer layer consists mostly of collagens, aligned with the longitudinal axis, and elastin,1–3 and is thought to serve a mostly structural (mechanical) role.4 The periosteum's innermost layer (closest to the bone) consists mostly of progenitor cells that constantly build1 and repair bone.5–7 This tissue is highly vascularized, and its preservation is crucial for normal bone repair. Periosteum is rich in osteoblasts, which deposit new bone matrix in the outer cortex, and in osteoblast precursors. Although bone marrow-derived pluripotent cells have been mostly exploited in regenerative medicine to facilitate healing of orthopaedic injuries, the periosteum is now recognized as an attractive source of cells.8–10 Over the past decade, animal models have been developed to assess the mechanisms of skeletal stem/progenitor cell recruitment during bone repair and to test the therapeutic effects of skeletal stem/progenitor cells. Several studies revealed that the endogenous regenerative potential of periosteum is high compared to bone marrow and other cell sources.

Development

During long bone development, all the populations of osteoblasts within periosteum and osteoblasts at the endosteal and trabecular bone surfaces within the marrow, are derived from the embryonic perichondrium.11 Each skeletal element is derived from a mesenchymal condensation that gives rise to a cartilage template surrounded by the perichondrium (Fig. 1). Ossification of these elements begins with vascular invasion of the perichondrium followed by the invasion of hypertrophic cartilage in the center of the cartilage template.13 The vascular invasion is followed by rapid removal of the calcified cartilage matrix and its replacement by bone and bone marrow. This process of endochondral ossification is highly regulated by several signaling pathways, including Hedgehog, bone morphogenetic protein (BMP), TGF-beta, PTH/PTHrP, FGF, Wnt, Notch, and VEGF, that act at the levels of chondrocytes, perichondrium, and blood vessels, allowing the synchronization of cell differentiation in these adjacent tissues.14–19 Many cell types participate in this process with some differentiating locally and others brought by blood vessels, but lineage analyses show that osteoblasts all come from the perichondrium.11 Osteoblasts precursors originating from the perichondrium migrate along with blood vessels to form the primary ossification center.20 Thus, during development, osteoblasts within periosteum and bone marrow are derived locally from the initial mesenchymal condensations, and more specifically the perichondrium, without systemic contribution from invading blood vessels.
Figure 1. Development of the periosteum and its contribution to bone repair. Stages of long bone development including formation of the initial mesenchymal condensations, followed by the segregation of cartilage (pink) and perichondrium (blue), vascular invasion, and replacement of hypertrophic cartilage by bone and bone marrow. Osteoblasts within periosteum (blue), bone marrow, and endosteum (green) are derived from the embryonic perichondrium. In the adult, after bone injury, cells that form cartilage and bone in the fracture callus are recruited locally from periosteum, bone marrow, blood vessels (pericytes), and potentially other adjacent tissues such as muscle and fat. Cellular contribution from systemic sources is minimal (red dots). Figure modified from Ref.12. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/jor]
thumbnail image

Repair

In the adult, the stages of bone repair recapitulate the well-defined stages of bone formation during embryogenesis, except for the inflammatory response, which is critical for bone regeneration.21–26 During this initial phase of repair, skeletal stem cells are activated at the fracture site and differentiate into osteoblasts and chondrocytes that deposit the extracellular matrix necessary for bone bridging. Skeletal stem cells differentiate during the inflammatory phase of repair and are exposed to inflammatory cytokines, growth factors, and mechanical signals.27–35 How these cellular, molecular and mechanical signals influence the recruitment of skeletal stem cells remains largely unknown. Histologically, cells within the periosteum respond rapidly to these signals, as a periosteal reaction can be detected within 24–48 h post-injury.3637 In the absence of stabilization, this periosteal reaction is particularly robust leading to the formation of a large callus and healing via endochondral ossification.3637 When fractures are rigidly stabilized, cells in the periosteum are not stimulated as efficiently, and callus formation is minimal. In this mechanically stable environment, healing occurs essentially via intramembranous ossification.38 These differences in cellular response to mechanical signals reside mostly within the periosteum, as shown by the up-regulation of the BMP pathway within the periosteum during the first stage of healing in non-stabilized fractures.3940
The periosteum contains skeletal progenitors that play an important role in bone repair; however, their identity and relative contribution to healing compared to other cell sources are not well defined. Many sources of skeletal progenitors have been proposed to participate in adult bone repair, including the local bone marrow, periosteum, soft tissues, and blood vessel walls, as well as cells brought to the injury site via blood vessels. Several approaches have been used to determine the potential recruitment of cells from distant sites during fracture repair, including parabiosis, bone marrow transplantation, and intravenous injection of cells in animal models.41–45 These approaches suggest that cells recruited systemically are minimal contributors to cartilage and bone, but give rise mostly to inflammatory cells and osteoclasts.4647
The contribution of blood vessels themselves was addressed using genetic lineage tracing. Endothelial cells do not appear to transdifferentiate into skeletal progenitors involved in fracture healing as cartilage and bone within the callus are not derived from Tie2-expressing cells.48 Pericytes marked with smooth muscle actin, however, coincide with a population of endogenous mesenchymal progenitors and can largely contribute to fracture healing.49 The tissue origins of these mesenchymal progenitors are undetermined, yet they are likely derived from the local blood vessels around the fracture site. Other populations of mesenchymal stem cells expressing Mx1 exist within the bone marrow cavity and have osteogenic potential during the repair of calvarial defects.50 These types of studies provide new molecular tools to elucidate the mechanisms of skeletal stem cell recruitment during bone repair.
Lineage analyses based on bone grafting have also revealed that periosteum largely contributes to cartilage and bone within the callus compared to bone marrow and endosteum.5–85152 Cells within local marrow and endosteum form bone mostly within the marrow cavity, and do not migrate out of the marrow compartment to form callus.5 Thus, not only local tissues, but perhaps most importantly, the periosteum are key cellular contributors to bone repair (Fig. 1). The extent to which progenitors within marrow and periosteum exhibit distinct regenerative capacities has not been established. The tissue location may play an important role, as cells located in periosteum and marrow may not receive the same biological and mechanical signals upon injury. Understanding these differences may help define competent cell sources and ways to stimulate the regenerative capacities of mesenchymal stem cells from other tissues, such as muscle, fat, and umbilical cord. Research is underway to characterize the endogenous cell sources for bone repair, identify the molecular pathways controlling their recruitment, and apply this knowledge to bone tissue engineering approaches.1053–58

NEW APPROACHES TOWARD UNDERSTANDING SKELETAL REPAIR AND REGENERATION

Skeletal repair is a dynamic, well-orchestrated process that involves complex and spatiotemporally coordinated function of different cellular compartments and integrated molecular pathways. Understanding complex molecular and cellular interactions during healing represents a critical step toward developing effective treatment strategies for enhancing repair and reconstruction. Immediately following cortical bone injury, periosteum undergoes a series of changes to initiate endochondral and intramembraneous bone formation at the injury site. Both types of bone formation begin with intensive proliferation of periosteal progenitor cells. Cells near the cortical bone junction differentiate into chondroprogenitors, whereas cells at the periphery of the cortex furthest away from the junction adopt an osteogenic cell fate.
The contribution of the periosteal progenitors to callus formation was examined using a segmental bone graft transplantation model in mice.658 By transplantation of a Rosa26A bone graft, the study demonstrated a predominant contribution of periosteal progenitors to both endochondral and intramembraneous bone formation at the initiation of repair. By tracking the LacZ+ve cell fate, the study further suggested a research paradigm in which activation, expansion, and differentiation of periosteal stem/progenitor cells act as an essential step to build a template for subsequent neovascularization, bone formation, and remodeling. Understanding this progenitor cell-driven initiation process not only provides mechanistic insight into endogenous regeneration capacity of periosteum, but could also offer information for optimizing tissue engineering constructs for fabrication of a periosteum substitute for repair and reconstruction.

Bone Morphogenetic Proteins (BMPs)

Using genetically modified mouse models, a number of molecular pathways have been discovered to play a critical role in the initiation of periosteum-mediated regeneration. Among them, BMP-2 appears to be at the apex of the signaling cascade that initiates the cellular proliferation and differentiation of periosteal progenitors during repair and regeneration. Genetic deletion of BMP-2 gene via Prx-1-Cre in limb mesenchyme condensation is dispensable for development of long bones. However, long bone lacking BMP-2 expression develops spontaneous fractures in adult animals. Most strikingly, deletion of BMP-2 completely abolishes fracture callus formation, suggesting a critical role of BMP-2 in the initiation of repair.59 In a similar study in which BMP-2 was knocked out at the initiation stage of healing in adult animals using a Tamoxifen inducible CreER mouse model,6061 deletion of BMP-2 at the onset of healing completely abrogated both endochondral and intramembranous bone repair. Deletion of BMP-2 in periosteal progenitor cells not only blocked cellular differentiation, but also impaired proliferation and survival of the cells. Further tracking of the BMP-2 mutant cells in a chimeric periosteal callus showed that few mutant cells could differentiate into chondrocytes and osteoblasts, even when they were placed in a wild type host injury environment, indicating an essential role of endogenous BMP-2 signaling in the initiation of periosteal callus formation.
In addition to BMP-2, several key components of BMP family proteins and their corresponding receptors are found in the activated periosteum, including BMP-2, 3, 4, 5, 8, noggin, BMPRIA, BMPRII, and pSmad 1/5/8.40 The differential role of BMP isoforms in repair was examined using floxed mouse models that allowed conditional deletion of BMP isoforms via Prx-1Cre. BMP-4 and 6 were dispensable for repair whereas BMP-3 played a negative role for early periosteum development and potentially in postnatal repair and regeneration.62–64Transgenic mice overexpressing BMP3 via the type I collagen promoter displayed spontaneous rib fractures as early as E17.0. The fractures were due to defects in differentiation of the periosteum and late hypertrophic chondrocytes resulting in thinner cortical bone with decreased mineralization.

Hedgehog, Ihh Pathway

Downstream of BMPs, the hedgehog pathway, in particular the Ihh pathway has long been suspected to play a role in periosteum-mediated endochondral bone repair.242565–67 Both Shh and Ihh have been implicated in early embryonic development that suggests mesenchymal progenitor cell differentiation and self-renewal.68 Ihh plays a key role in perichondrium development and collar bone formation. Embryonic deletion of Ihh disrupts collar bone formation and early osteoblast development.69–71 Ihh is abundantly expressed in prehypertrophic and hypertrophic chondrocytes in callus. Using in situ hybridization and Ptc-LacZ staining, a recent study from Zhang et al. further showed that Ihh was expressed in nascent cartilaginous tissues in periosteum callus adjacent to the bone surface at the initiation stage of healing. These hedgehog producing cells send out signals to the surrounding chondroprogenitors, osteoblast progenitors as well as cells associated with early invading vessels.72
To further determine the role of hedgehog pathway in postnatal periosteum-mediated repair and regeneration, Wang et al. isolated a unique population of mesenchymal progenitors from day 5 autograft periosteum. These isolated periosteal cells expressed mesenchymal progenitor cell markers: SSEA4, CD105, CD29, CD140b, and ScaI. They could further give rise to osteoblasts, chondrocytes and adipocyte in vitro. Compared with mesenchymal progenitors isolated from other tissues, such as adipose and bone marrow, these cells showed stronger responsiveness to both BMP-2 and hedgehog agonists. Overexpression of Shh N-terminal peptide, a hedgehog agonist, in these cells induced robust ectopic bone formation in nude mice. Further deletion of Smoothened1, a receptor that transduces all hedgehog signaling, using a Tamoxifen inducible CreER mouse model significantly reduced periosteal bone formation in the conditional knockout mice.72 These studies indicate an important role of hedgehog pathway in periosteum-mediated repair and regeneration. Further studies are necessary to determine the potential use of hedgehog agonists in repair and in bone tissue engineering applications.

Cyclooxygenase-2, COX-2

COX-2 is discovered as an inducible isoform of cyclooxygenase in the prostaglandin biosynthesis pathway. As an immediate early gene, COX-2 is induced by a variety of inflammatory cytokines and growth factors, including bone anabolic factors FGF, IGF, TGF-β, and BMP-2.73–76 COX-2 induction was localized in chondroprogenitors, proliferating chondrocytes, and osteoblasts, concomitant with the initiation of endochondral and intramembraneous bone formation in periosteum.51 Although deletion of COX-2 has no discernible effect on postnatal bone development, deletion of COX-2 globally or specifically in mesenchyme or cartilage significantly impairs periosteal progenitor cell proliferation and delays subsequent endochondral and intramembranous repair.2151 The critical role of COX-2 in repair was further illustrated in a study of fracture healing in aged mice. In comparison to young mice, aged mice elicited a mitigated induction of COX-2 during early endochondral bone formation. Treatment of aged mice with an agonist of prostaglandin receptor type 4 receptor (EP4) rescued the delayed endochondral bone formation,77 suggesting a beneficial effect of targeting EP receptor for improved healing.

Wnt Signaling Pathway

Wnt/β-catenin, a critical player in osteoblast differentiation and bone formation, has recently emerged as a potential therapeutic target for bone repair and fracture healing.7879 The Wnt pathway plays a key role in bone and cartilage development. Activation of the Wnt pathway favors osteoblastic differentiation, but inhibits chondrogenesis.8081 Multiple Wnt proteins and their modulators are expressed in periosteum.82 Although the detailed molecular actions of Wnt pathway on different phases of endochondral bone repair remain to be determined, genetic manipulation of Wnt signaling in mice show that inhibition of Wnt/b-catenin could suppress early chondrogenesis but favor osteogenesis, leading to accelerated fracture repair.8384 Consistently, delivery of a Wnt/β-catenin inhibitor DKK1 suppressed bone repair, whereas administration of a DKK1 neutralizing antibody improved repair and regeneration.828586 Interestingly, several pathways known to stimulate fracture repair, including the BMP-2 and Hh pathways, enhance the Wnt/β-catenin pathway.878872 In addition, intermittent PTH treatment strongly stimulated fracture healing in part by inducing canonical Wnt signaling.89 Prostaglandin E2, the major metabolite from COX-2 enzymatic activity, also activates canonical Wnt signaling via EP2 and EP4 receptors.90 How these pathways converge on Wnt/β-catenin to enhance repair has become the focus of intensive studies.

SURGICAL AND ENGINEERING APPROACHES TO ELUCIDATE AND UNLEASH THE REGENERATIVE POWER OF THE PERIOSTEUM

The periosteum is a composite tissue12 that provides a niche for pluripotent osteochondroprogenitor cells and exhibits a remarkable capacity to generate bone de novo within critical sized defects. Surgeons have harnessed this regenerative capacity for more than a century.91–93 Recent studies have focused on the mechanisms underlying periosteum's remarkable regenerative capacity, and in particular the role of mechanical and mechanically modulated signals in this process.

Periosteum's Regenerative Capacity

A recently described case study94 demonstrating the capacity of the periosteum in situ to regenerate a several inch segment of resected fibula provided the inspiration for a one stage bone transport procedure,95 which has provided a new platform to elucidate the role of specific biological and mechanical fractures in critical-sized long bone defect repair in large mammals.9697 In this procedure (Fig. 2A), a solid, reamed intramedullary nail fills the medullary cavity, stabilizing the femur. Proximal to the defect, the periosteum is carefully lifted and peeled back, maintaining the blood supply but disrupting the Sharpey's fibers that anchor the periosteum to the underlying bone. Osteotomy then produces a periosteum denuded bone segment, which is transported and docked distally to fill the original defect. The periosteum is then sutured closed in situ around the newly created defect zone and to the denuded bone segment, forming a sleeve around the haematoma or autologous graft filled defect.95 When treated this way, de novo bone completely bridges the defect after 16 weeks, even in the absence of the medullary cavity, which is filled by the nail. Interestingly, filling the periosteum-enveloped defect with graft retards the time for infilling by periosteum (Fig. 2B).9395 Slowing of the healing response may be attributed to, on the one hand, an increased resistance to cellular egression and mass transport from the periosteum to the defect. On the other hand, the bone graft filling the defect must be resorbed prior to vasculogenesis and new bone apposition, requiring additional healing time.93
Figure 2. One stage bone transport model to harness the regenerative capacity of the periosteum provides an in vivo platform to elucidate the role of specific biological and mechanical factors in critical-sized long bone defect healing. (A) Surgical procedure, where (A1) the periosteum proximal to the defect is peeled back, and an osteotomy is performed, after which the denuded bone segment is transported distally and docked (A2), filling the original defect zone and creating a new, more proximal defect. The periosteum is then sutured in place in situ, forming a sleeve around the new, haematoma-filled defect. The entire construct is stabilized by an interlocked intramedullary nail. (B) Addition of factors to the periosteal sleeve model, including morcelized autologous bone graft from the iliac crest and bone chips adhering in situ to the inside of the periosteal sleeve, results in better bone infilling and defect healing than the baseline control. Groups with adherent bone chips but without morcelized graft showed the best healing at 16 weeks. (C) Addition of factors to the periosteum substitute model show an improvement in healing with increasing numbers of factors added, including periosteum-derived cells seeded on collagen membranes and the inclusion of periosteal strips. (D) The periosteum substitute implant exhibits a modular design for inclusion of desired periosteal factors and/or pharmaceuticals. Figure modified from Refs.96102 [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/jor]
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Clinical reports and recent experiments indicate that mechanical loading enhances the regenerative capacity of the periosteum. In studies using the previously described experimental platform, prevailing mechanical loads and proximity to the periosteum were hypothesized to modulate early bone generation in the defect zone and late measures of healing and remodeling of autograft in the denuded bone transport segment.939596 Quantifying the area (a measure of bone quantity) and concentration (a measure of bone quality) of calcein green fluorochrome, which was administered in the first 2 weeks after surgery, allowed for correlation of new bone formation to both loading history and proximity to the periosteum. The laser confocal microscope was used as a spectroscope to measure the intensity of the fluorochrome signal as a function of distance from the periosteum; the intensity of fluorescence in a single focal plane indicates the concentration or amount of mineral chelation by the fluorochrome.93 Further, the major and minor centroidal axes of the long bone cross-section indicate axes about which the bone is most and least resistant to bending loads, respectively.
Using these measures to compare groups treated with and without packed morcelized bone graft, the amount of early bone formation was significantly higher along the bone axis most resistant to bending loads (major centroidal axis), but the quality of early bone formed (density as measured by intensity or concentration of mineralized tissue) was higher along the bones axis least resistant to bending loads (minor centroidal axis). Finally, the spatial distribution of new bone formed in the first weeks after surgery correlated significantly with the distance from the periosteum and prevailing mechanical loads.93 Interestingly, although the periosteum itself regenerates in the denuded bone segment after the one stage bone transport procedure, the thickness of the regenerated periosteum did not correlate to prevailing mechanical loads.98
Based on the aforementioned studies, factors inherent to the periosteum, including the ingression of pluripotent cells from the periosteum, drive the process. Although correlation does not equal causation, ongoing studies aim to elucidate mechanistic relationships between mechanical loading, transport of cells and molecular factors, and de novo generation of tissue in critical sized bone defects.
The regenerative capacity of the periosteum exhibits great clinical promise for treatment of non-unions and tissue defects occurring due to tumor resection, infection, trauma, and congenital defects. The approach exemplified by the one stage bone transport procedure has been implemented successfully in limited clinical cases where other treatment modalities were not feasible.100 Engineering of substitute periosteum is a promising area of research that benefits from both top down perspectives and bottom up approaches to recreate the multiscale structure–function relationships embodied by the smart material, using nature's engineering paradigms (Fig. 2C and D).101–105

Mechanical and Permeability Properties of Periosteum

An understanding of periosteum's mechanical properties and the local mechanical environment of its progenitor cells is important to understand and harness periosteum's mechanobiology and regenerative capacity. In a series of recent studies, Knothe Tate's lab showed that periosteum is hypoosmolaric (swells in phosphate buffered saline), pre-stressed, and anisotropic; periosteum shrinks twice as much in the axial than in the circumferential direction when released from the underlying bone, which is indicative of pre-stress in the tissue.103104 Furthermore, the elastic modulus is ten times greater in the axial direction and exhibits strain stiffening at loading rates corresponding to trauma. These anisotropic properties are expected to profoundly influence bone mechanobiology, during development, growth, and healing, in both health and disease.103
The multiscale permeability properties of periosteum are intriguing. Periosteum tissue exhibits barrier properties, such as swelling under isotonic conditions and physiological pH.103105 Furthermore, periosteum permeability is modulated by stress and is directionally dependent as well as site specific. For example, the permeability of the ovine femur is significantly more permeable in the bone → muscle direction when pre-stress is maintained throughout testing. When periosteum pre-stress is not maintained,105 it is more permeable in the muscle → bone direction. At a cell-molecular scale, recent Western blot experiments show that periosteum derived cells express proteins for zona occludens 1 (ZO-1, a tight junction protein) and N-cadherin (an adherens junction protein), both of which are necessary for the formation of tight junctions, which confer barrier properties to tissues.106
Prevailing stress also appears to modulate periosteum behavior. High resolution optical strain mapping of the local mechanical milieu of cells within the periosteum shows that bone generation in defects correlates to regions of native, intact periosteum experiencing the greatest net change in strain.99