Fibrous Scar Tissue Formation Research Articles

Xenopus Laevisas a Novel Model to Study Long Bone Critical-Size Defect Repair by Growth Factor-Mediated Regeneration

We used the tarsus of an adult Xenopus laevis frog as an in vivo load-bearing model to study the regeneration of critical-size defects (CSD) in long bones. We found the CSD for this bone to be about 35% of the tarsus length. To promote regeneration, we implanted biocompatible 1,6 hexanediol diacrylate scaffolds soaked with bone morphogenetic proteins-4 and vascular endothelial growth factors. In contrast to studies that use scaffolds as templates for bone formation, we used scaffolds as a growth factor delivery vehicle to promote cartilage-to-bone regeneration. Defects in control frogs were filled with scaffolds lacking growth factors. The limbs were harvested at a series of time points ranging from 3 weeks to 6 months after implantation and evaluated using micro-computed tomography and histology. In frogs treated with growth factor-loaded scaffolds, we observed a cartilage-to-bone regeneration in the skeletal defect. Five out of eight defects were completely filled with cartilage by 6 weeks. Blood vessels had invaded the cartilage, and bone was beginning to form in ossifying centers. By 3 months, these processes were well advanced, and extensive ossification was observed in 6-month samples. In contrast, the defects in control frogs showed only formation of fibrous scar tissue. This study demonstrates the utility of a Xenopus model system for tissue engineering research and that the normal in vivo mechanism of endochondral bone development and fracture repair can be mimicked in the repair of CSD with scaffolds used as growth factor delivery mechanisms.

Late onset cervical myelopathy secondary to fibrous scar tissue formation around the spinal cord stimulation electrode

Case report. To report the late onset of cervical myelopathy secondary to fibrous scar tissue formation around an epidural electrode implanted for spinal cord stimulation (SCS). Department of Orthopaedic Surgery, Hoshigaoka Koseinenkin Hospital, Osaka, Japan. A 49-year-old man who had an electrode implanted for SCS 5 years ago was referred to our department on 2 March 2005, complaining of difficulty using chopsticks and walking. A computed tomography scan with myelography revealed severe spinal cord compression around the epidural electrode. Surgical removal of the electrode was not effective. Removal of fibrous scar tissue during a second surgery significantly improved his neurological symptoms. Late onset cervical myelopathy secondary to fibrous scar tissue formation around the epidural electrode should be considered a possible event associated with SCS therapy.

Presurgical and Postsurgical Orthodontics in Patients With Cleft Lip and Palate

Patients with cleft lip and palate (CLP) usually have skeletal Class III malocclusion with maxillary deficiency due to the cleft itself and fibrous scar tissue formation caused by the reconstructive surgery. In adult CLP patients with excessive jaw discrepancies, orthognathic surgery is often indicated to correct their functional and esthetic problems. However, CLP patients have different inherent structures that may require a strategic approach compared with noncleft Class III patients. Main differences in skeletal and dental findings of lateral cephalograms between CLP and noncleft Class III surgical patients are to be demonstrated. Furthermore, a strategic approach with various mechanics in the presurgical orthodontic stage will be applied to suit the distinct characteristic of the case. Successful clinical outcome was critically dependent on the close communication among the related specialists.

Matrix Metalloproteinase-1 Promotes Muscle Cell Migration and Differentiation

Injured skeletal muscle has the capacity to regenerate through a highly coordinated sequence of events that involves both myoblast migration and differentiation into myofibers. Fibrosis may impede muscle regeneration by posing as a mechanical barrier to cell migration and fusion, providing inappropriate signals for cell differentiation, and limiting vascular perfusion of the injury site, subsequently leading to incomplete functional recovery. Our previous studies demonstrated that matrix metalloproteinase-1 (MMP-1) is able to digest fibrous scar tissue and improve muscle healing after injury. The goal of this study is to investigate whether MMP-1 could further enhance muscle regeneration by improving myoblast migration and differentiation. In vitro wound healing assays, flow cytometry, reverse transcriptase-polymerase chain reaction (RT-PCR), and Western blot analyses demonstrated that MMP-1 enhances myoblast migration but is not chemoattractive. We discovered that MMP-1 also enhances myoblast differentiation, which is a critical step in the sequence of muscle regeneration. In addition, RT-PCR and Western blot analyses demonstrated the up-regulation of myogenic factors after MMP-1 treatment. In vivo, we observed that myoblast transplantation was greatly improved after MMP-1 treatment within the dystrophic skeletal muscles of MDX mice. MMP-1 may therefore be able to improve muscle function recovery after injury or disease by increasing both the number of myofibers that are generated by activated myoblasts and the size of myoblast coverage area by promoting migration, thus fostering a greater degree of engraftment.

Immobilization Modulates Macrophage Accumulation in Tendon-Bone Healing

Tendon-to-bone healing occurs by formation of a fibrous, scar tissue interface rather than regeneration of a normal insertion. Because inflammatory cells such as macrophages lead to formation of fibrous scar tissue, we hypothesized immobilization would allow resolution of acute inflammation and result in improved tendon-bone healing. We reconstructed the ACL of 60 Sprague-Dawley rats using a tendon autograft. An external fixation device was used to immobilize the surgically treated knee in 30 rats. We evaluated tendon-bone interface width, collagen fiber continuity, and new osteoid formation histologically. Immunohistochemistry was used to localize ED1+ and ED2+ macrophages at the tendon-bone interface at 2 and 4 weeks. Biomechanical testing was performed at 4 weeks. Interface width was smaller and collagen fiber continuity was greater in the immobilized group. Immobilized animals exhibited fewer ED1+ macrophages at the healing interface at 2 and 4 weeks. In contrast, there were more ED2+ macrophages at the interface in the immobilized group at 2 weeks. Failure load and stiffness were similar between groups at 4 weeks. The data suggest early immobilization diminishes macrophage accumulation and may allow improved tendon-bone integration.

Augmentation of Tendon-to-Bone Healing with a Magnesium-Based Bone Adhesive

Background Healing of an anterior cruciate ligament graft in a bone tunnel occurs by formation of fibrous scar tissue, which is weaker than the normal fibrocartilaginous insertion. Hypothesis We hypothesized that a magnesium-based bone adhesive would improve tendon-to-bone healing in a rabbit anterior cruciate ligament reconstruction model. Study Design Controlled laboratory study. Methods Thirty-five New Zealand White rabbits underwent bilateral anterior cruciate ligament reconstructions with semitendinosus autografts. A total of 12.5 g of bone adhesive was placed in the intraosseous tunnel around the graft in one limb, while the tunnels in the contralateral limb received no implant. Sixteen animals each were sacrificed at 3 weeks and at 6 weeks (12 biomechanical testing/4 histology). Outcomes included semiquantitative histologic analyses for new cartilage formation and fibrous tissue formation in the tendon-bone interface, microcomputed tomography to quantify new bone formation along the bone tunnel, and biomechanical testing of load-to-failure and stiffness. Three animals were sacrificed at time 0 to confirm adequate tunnel fill with the bone adhesive on microcomputed tomography. Results All specimens had adequate tunnel fill with the bone adhesive at time 0. Application of the bone adhesive resulted in more cartilage formation and less fibrous tissue formation at the tendon-bone interface at 6 weeks compared with controls (P < .05). There was significantly more bone formation in the tibia of the treated limbs at 6 weeks (P = .01). The load-to-failure was significantly higher in the treated group at 6 weeks (71.8 ± 31.8 N vs 43.4 ± 14.8 N; P = .04). There were no differences in stiffness at either time point, and there were no differences at 3 weeks in any outcome variable. Conclusion The magnesium-based bone adhesive improves tendon-to-bone healing based on histologic and biomechanical testing at 6 weeks in a rabbit model of anterior cruciate ligament reconstruction. Clinical Relevance Further studies are needed to investigate the clinical potential of this bone adhesive to enhance healing and decrease recovery time in soft-tissue ligament reconstruction.

The Effect of Bone Morphogenetic Proteins in Fracture Healing

Bone is unique in its selfhealing capacity as it heals without fibrous scar tissue formation. The process resembles the embryonic bone formation in utero, either via the intramembranous or the endochondral route; in fracture healing cells migrate in and differentiate from mesenchymal stem cells into mature osteoblasts or chondroblasts, forming a callus. By remodelling and later modelling bones unite without a scar and in some cases even without radiographic traces. When healing does not occur, the consequences of a fracture may be detrimental to the individual: leaving a true pseudarthrosis, or a malunited bone resulting in poor function and destruction of joints, or infection of the fracture which may lead to permanently draining sinuses or even amputation. Nature’s capacity to heal bones is enormous and therefore our job as surgeons to promote healing is in most cases quite simple. Fractures should be reduced to as close an anatomical position as possible, and immobilised for a certain period of time until enough callus to carry load has been formed. During the 20th century methods for fracture fixation became more sophisticated, and for certain fractures this has changed the outcome dramatically. Our understanding of fracture healing has also improved; the molecular mechanisms and the sequences of healing are partially known. However, we still poorly understand why fractures do not unite in every case, even if a large fracture gap, a poorly reduced fracture or improper immobilisation regularly lead to delayed union or nonunion (1). Since a significant part of fractures does not heal properly, there is still a need for augmentation of the bone healing process. In 1965 Marshall Urist coined the term bone morphogenetic protein when he detected that a protein extract from bone lead to new bone formation in muscle (2). In the 1980’s the amino acid structures of the bone morphogenetic proteins were detected, and the proteins were sequenced and cloned. In the 1990’s, after pre-clinical testing in animals from mouse to non-human primates, recombinant proteins started to be tested in human models. Recombinant human bone morphogenetic protein 2 (rhBMP-2) and recombinant human bone morphogenetic protein 7 (rhBMP-7) or osteogenic protein 1 (OP-1) has so far been used clinically. At present, there are several published clinical studies on the effects of BMPs in bone healing or in delayed unions/ non-unions and several studies have reported the effects in fusion of the lumbar spine (3–5). In this review the clinical studies published on long bone healing will be summarized; one study on fibular osteotomies, one study each on the BMPs used in tibial pseudarthrosis or in allograft pseudarthrosis and two studies on acute tibial fractures (6–10). In the present review BMP denotes the recombinant human proteins and not the term that Urist coined; rhBMPs are not necessarily identical to the proteins produced in the human body as there are posttranslational modifications of the proteins in vivo that do not take place when produced in vitro (phosphorylations and glucosylations of the protein). The amino acid sequence of the rhBMPs is though identical to the ones produced in vivo.

Facilitated migration of cells from a transected peripheral nerve over collagen fibers: in vivo observations

In cases of peripheral nerve damage the gap between proximal and distal stumps can be closed by suturing the ends together, using a nerve graft, or by nerve tubulization. Suturing allows regeneration but does not prevent formation of painful neuromas which adhere to adjacent tissues. Autografts are not reported to be as good as tubulization and require a second surgical site with additional risks and complications. Tubulization involves implanting a nerve guide tube that will provide a stable environment for axon proliferation while simultaneously preventing formation of fibrous scar tissue. Supplementing tubes with a collagen gel or collagen plus extracellular matrix factors is reported to increase axon proliferation when compared to controls. But there is no information regarding the use of collagen fibers to guide nerve cell migration through a tube. This communication reports ultrastructural observations on rat sciatic nerve regeneration through a silicone nerve stent containing crosslinked collagen fibers.Collagen fibers were prepared as described previously. The fibers were threaded through a silicone tube to form a central plug. One cm segments of sciatic nerve were excised from Sprague Dawley rats. A control group of rats received a silicone tube implant without collagen while an experimental group received the silicone tube containing a collagen fiber plug. At 4 and 6 weeks postoperatively, the implants were removed and fixed in 2.5% glutaraldehyde buffered by 0.1 M cacodylate containing 1.5 mM CaCl2 and balanced by 0.1 M sucrose. The explants were post-fixed in 1% OSO4, block stained in 1% uranyl acetate, dehydrated and embedded in Epon. Axons were counted on montages prepared at a total magnification of 1700x. Montages were viewed through a dissecting microscope. Thin sections were sampled from the proximal, middle and distal regions of regenerating sciatic plugs.

Modes of healing histologically after endodontic surgery in 70 cases

The histologic changes in humans after endodontic surgery were studied in 70 biopsies of the root apex and surrounding soft tissues and bone obtained from less than one year to 14 years after the surgical procedures. The following aspects were examined: degree of inflammation, formation of new cementum, root resorption, regeneration of the periodontal ligaments, formation of fibrous scar tissue, ankylosis, presence of granulation tissue and epithelial proliferations, and regeneration of new bone. The histologic examination revealed thaf the results of periapical surgery could be divided into three main types: (1) healing with re-formation of the periodontal membrane or ankylosis, and no or mild periapical inflammation, (2) healing with fibrous tissue (scar tissue) in communication with or adjacent to the periodontal membrane, occasional ankylosis, and varying grades of inflammation, and (3) moderate or severe periapical inflammation without scar tissue.

Roentgen Localization of Myocardial Damage Resulting from Coronary Artery Disease

CORONARY occlusion produces destructive changes in the myocardium, the degree and extent of damage depending on the size of the vessel occluded and the rapidity of obstruction. With sudden blocking of a coronary artery, there is early degeneration of the muscle fibers. According to Mallory and White (7), necrosis occurs within 24 hours. At this time there is an infiltration of polymorphonuclear leukocytes. About the second week there is cessation of leukocytic invasion and an appearance of phagocytes and new blood vessels. In the third week there is laying down of scar tissue, with invasion of fibroblasts and collagen. In the fourth week and thereafter, collagen steadily increases in amount and density and the earlier reaction subsides. In the second month, healing is, as a rule, complete, the site of infarction being marked by fibrous scar-tissue formation. If the obstructed vessel is large, it may result in almost immediate death. The more common type, however, is a gradual, perhaps insidious, narrowing, which produces small progressive degenerative lesions in the heart muscle (Fig. 1). The changes, however, are compatible with life. In these cases, collateral circulation is established so that the heart may continue to function at a lower level of efficiency. This type of case is particularly apt to escape attention of the physician and patient, the symptoms frequently being vague, or suggestive of disease in the gastro-intestinal or biliary tracts. The value of roentgen study in the diagnosis of coronary disease has already been established. The purpose of localization of the area of myocardial infarction tends to serve two functions: (1) it is conducive to more accurate diagnosis which should make possible earlier treatment of the disease; (2) it is of value in those cases selected for operation for the purpose of establishing new circulation to the heart. Wearn (10) writes as follows: “The right coronary artery (Fig. 2-A) arises from the anterior aortic sinus and emerges on the surface of the heart between the right auricle and conus arteriosus (2). Then, lying in the coronary sulcus, it runs to the right and downward where it rounds the acute margin to the diaphragmatic surface of the heart. It continues in the coronary sulcus from right to left to the region of the junction of the auricles and ventricles where it turns to run down the interventricular groove as the posterior branch, and terminates near the apex. In its course, it gives off small branches to the left auricle. Usually, as it rounds the acute margin of the heart, it gives off a large branch called the marginal artery, which, in turn, gives off numerous branches to the right ventricular wall. In its course down the interventricular sulcus, the posterior descending branch gives off many large branches to the right ventricle, to the septum, and to that part of the left ventricle adjoining the septum near the apex.