Gene therapy to improve osteogenesis in bone lesions with severe soft tissue damage

Background Ex vivo gene therapy can induce bone formation when delivery cells carrying the bone morphogenetic protein (BMP) gene are used. The hypothesis for this study was that the cell-mediated gene therapy could improve the healing of bony lesions with severe soft tissue damage.Method An animal model with a femoral osteotomy lesion associated with soft tissue damage was developed in rats. Muscle-derived cells, genetically engineered to express BMP4, were inserted within the osteotomy gap. Cells genetically engineered to express LacZ were used for the control group. The groups were subdivided with regard to the fixation method: stable and unstable fixation. The rats were killed for histological and radiographic evaluation 3 and 6 weeks post-surgery.Results No callus formation was found in the control group at any time point, whereas sufficient callus formation appeared in the treatment group after 6 weeks. A bridging callus with woven bone and hypertrophic chondrocytes was achieved in the treatment group when a stable fixation was used, but failed to appear in unstable fixation.Conclusion The combination of muscle-derived cells expressing BMP4 and a stable fixation were able to bridge the bone defect within 6 weeks, but with prolonged osteochondral ossification. Therefore, the ex vivo gene therapy could be an efficient biological approach to improve the treatment of bone lesions with severe soft tissue damage.     

Osseous interference of soft tissue healing

Bone may interfere with soft tissue wound contracture by osteomyelitis or unyielding rigidity. Chronic osteomyelitis and nonhealing cavities are being successfully treated by debridement, coverage or fill by permanently pedicled flaps, and appropriate antibiotics.     

Growth factors improve muscle healing in vivo

Injury to muscles is very common. We have previously observed that basic fibroblast growth factor (b-FGF), insulin growth factor type 1 (IGF-1) and nerve growth factor (NGF) are potent stimulators of the proliferation and fusion of myoblasts in vitro. We therefore injected these growth factors into mice with lacerations of the gastrocnemius muscle. The muscle regeneration was evaluated at one week by histological staining and quantitative histology. Muscle healing was assessed histologically and the contractile properties were measured one month after injury. Our findings showed that b-FGF, IGF and to a less extent NGF enhanced muscle regeneration in vivo compared with control muscle. At one month, muscles treated with IGF-1 and b-FGF showed improved healing and significantly increased fast-twitch and tetanus strengths. Our results suggest that b-FGF and IGF-1 stimulated muscle healing and may have a considerable effect on the treatment of muscle injuries.     

Effects of low-level laser therapy on soft and hard tissue healing after endodontic surgery

The aim of this prospective study was to examine possible benefits of low-level laser therapy (LLLT) on soft and hard tissue healing after endodontic surgery. Seventy-six endo-surgery cases on maxillary incisors were included. The patients were assigned randomly into control and laser groups. In the laser group, gallium-aluminum-arsenide (GaAlAs) diode laser irradiation (810 nm, 129 mW, 3.87 J/cm²) was performed immediately after surgery and daily for postoperative 7 days from buccal and palatal surfaces (5 min for each side). In the control group, patients were not subjected laser therapy. The patients were compared in terms of pain, clinical and radiological findings, and life quality indexes [Oral Health Impact Profile-14 (OHIP-14) and General Oral Health Assessment Index (GOHAI)]. Seventy-one patients completed the study (n?=?37 for control group, n?=?34 for laser group). The laser group showed better results in edema, wound healing, and the number of analgesic tablets used on the 1st, 3rd, and 7th postoperative days. Significant reduction in ecchymoses was observed in the laser group on the postop 3rd and 7th days. The patients had significantly lower pain on the 1st and 3rd postop days in laser group. The laser group showed significantly better results in OHIP-14 and GOHA indexes on postop days 1 and 3. The laser group showed significantly favorable results in terms of bone density, defect volume and area, and periapical index in the postop 3rd month. This study concluded that LLLT improved soft and hard tissue healing after endodontic surgery and also showed favorable effects on pain and life quality of patients especially in the early phase of healing period.     

Current concepts in soft connective tissue wound healing

The strength and integrity of intact soft connective tissues are related to the forces which exist between collagen fibrils and these in turn appear to depend on collagen fibril size, density and architecture en masse. The genetic type of collagen, enzymic modifications to the collagen monomer and the proteoglycan environment all affect fibril size. Current evidence suggests that the restoration of tissue continuity and the early redevelopment of tissue strength following wounding are initially achieved by the formation of a myofibroblast-reticulin network which eventually disappears as the healing wound ages. The extent of this network defines the area in which repair tissue will be laid down and the network is equipped with the sensory apparatus to monitor the physical and chemical environment where healing is taking place and thus to direct the various facets of connective tissue synthesis outlined above. The maturation of the scar connective tissue matrix and the development of attachment between new and original connective tissues are simultaneous, related but independent processes. It takes some time before the weld is achieved by the same forces that hold connective tissue fibres together in intact tissues and the myofibroblast-reticulin network is replaced.     

Revascularisation during fracture healing with soft tissue injury

Introduction  The purpose of our study was to quantitatively assess changes in the revascularisation process in the fracture gap and in adjacent regions during the course of healing of diaphyseal fractures with and without closed soft tissue injury. Methods  In a rat model (fracture n = 26; fracture with closed soft tissue crush n = 26) revascularisation was assessed in a long-term study with regional mapping by laser Doppler flowmetry, the healing outcome being mechanically tested after 4 weeks. Fracture and soft tissue crush were performed by modified controlled impact device. Results  No differences in blood circulation were observed at the fracture gap between the study groups up to day 28. In the proximal region of the fracture, the blood circulation in the group with additional soft tissue trauma was down to the baseline throughout the investigation period while the values in the fracture group led to a hyperperfusion after 3 and 7 days. In the distal part at day 1, the blood flow was strongly depressed after fracture, while microcirculation with an additional soft tissue trauma showed only a moderate decline. The reduction of blood circulation in the soft tissue corresponded to the extent of trauma. Mechanical testing demonstrated no significant difference in failure load or in flexural rigidity. Conclusion  Our results indicate that damage severe soft tissue does not adversely affect the fracture healing process. Furthermore, the present findings suggest that a partly destroyed bone–soft tissue interaction resulting in only a temporary and slight reduction of the extraosseous blood supply might have no deteriorating effect on fracture healing outcome. A possible delay in healing is not observed during the first 4 weeks. Therefore, soft tissue damage without destruction of the bone–soft tissue interface is likely to have only a limited effect on fracture healing.     

Growth factor impact on wound healing

Sixty thousand to 118,000 lower extremity amputations are performed each year in the United States. The combination of peripheral vascular disease and diabetes mellitus accounts for most cases, with diabetic patients representing 45% to 70% of all nontraumatic, lower extremity amputations. The 3-year survival rate after amputation is only 50%. As podiatric physicians, we are directly involved in limb preservation. Progress has occurred in both the diagnosis and treatment of lower extremity, chronic, nonhealing ulcers. An aggressive, comprehensive amputation intervention program is critical to those patients with refractory wounds to prevent the emotional, functional, and economic costs of limb loss. Recent developments in recombinant growth factors are making it possible to decrease the morbidity and mortality associated with defective angiogenesis, fibroblastic proliferation, collagen remodeling, and epithelial regeneration. Widespread use of growth factors will first occur in topical applications. Absorbable sutures, as well as impregnated bandages, are a likely method of delivering the growth factors to the wound site. Biotechnology companies are developing a stable formulation for bFGF topical application. Clinical trials have begun at various teaching hospitals across the United States for treatment of venous stasis ulcers. U.S. and European firms are collaborating to conduct the clinical studies required to obtain regulatory approvals leading to the sale of topical recombinant bFGF. Although U.S. approval is pending, European use of EFG in the healing of corneal incisions began several years ago. In the future, use of recombinant EGF topically with burn patients may permit earlier reharvesting of healed donor sites as well as coverage of larger graft areas. As some growth factors affect specific processes of healing and cell types, it may be necessary to combine growth factors for complex wounds. PDGF application in combination with other growth factors to incisional wounds may decrease postoperative complications with wound dehiscence while mediating inflammation and repair. In vivo experimental findings suggest that combinations of PDGF and insulin applied topically to wounds may increase the rate of wound repair in diabetics. It is also possible that even the normal healing process may be accelerated, thereby shortening postsurgical convalescence. Approval for internal administration of growth factors will require additional research and thorough clinical trials. The ability of TGF-beta to promote collagen formation may also relate to a metabolic condition such as osteoporosis, in which inadequate formation of collagen or other components of the bone matrix may contribute to pathogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Basic fibroblast growth factor may improve devascularized sternal healing

BACKGROUND: We have shown that a gelatin sheet incorporating basic fibroblast growth factor enhanced bone regeneration of the devascularized sternum. The purpose of this study was to determine if topical use of the gelatin sheet accelerated normal sternal regeneration and bone remodeling. METHODS: Thirty Wistar rats had median sternotomy and were divided into 3 groups: 10 had the bilateral internal thoracic arteries removed and basic fibroblast growth factor sheet applied on the sternum (group A), 10 had just the bilateral internal thoracic arteries removed (group B), and 10 had intact bilateral internal thoracic arteries (group C). RESULTS: Four weeks later the peristernal blood flow significantly increased and marked angiogenesis was seen around the sternum in group A. Histologically, the sternum was almost completely healed only in group A. In group A the bone mineral content was highest, but the bone mineral density was similar to that in other groups. The osteoclast index in group A was highest at the border zone of bone formation and remained high in regenerated bone. CONCLUSIONS: The basic fibroblast growth factor sheet offset sternal ischemia and accelerated normal sternal bone regeneration and remodeling, not only by callus formation but also by callus resorption.     

Radiation therapy for low-grade soft tissue sarcoma

One hundred eight patients with low-grade soft tissue sarcoma treated at the authors' institution from 1984 to 1999 were reviewed retrospectively. Low-grade sarcomas were defined as those designated as Grade I of III or Grade I or II of IV. Patients who presented with recurrent tumors or who had multiple procedures at outside institutions were excluded. The patient's gender, age at diagnosis, histologic diagnosis, site and depth of primary involvement, and specimen size at resection were noted. Involvement of periosteum, bone, and neurovascular structures also was recorded. The decision to use radiation therapy was made case-by-case. Indications for preoperative radiation therapy included tumor adjacent to the neurovascular bundle or bone where a marginal surgical margin was anticipated. Indications for postoperative radiation therapy included followup resection of an unsuspected malignancy. Patients were evaluated according to treatment rendered. Sixty-six patients were treated with surgery alone, whereas 42 patients had excision of the tumor in conjunction with radiation therapy. The overall local control rate was 97.2% (105 of 108). There were no statistically significant differences in local recurrence, wound complication, fibrosis, or survival between the two groups. Patients treated with radiation therapy had an increased incidence of postoperative lymphedema. Kaplan-Meier 10-year survival rates were approximately 90% for both groups.     

Hyperbaric oxygen therapy in necrotizing soft tissue infections

BackgroundSurgical debridement and antibiotics are the mainstays of therapy for patients with necrotizing soft tissue infections (NSTIs), but hyperbaric oxygen therapy (HBO) is often used as an adjunctive measure. Despite this, the efficacy of HBO remains unclear. We hypothesized that HBO would have no effect on mortality or amputation rates.MethodsWe performed a retrospective analysis of our institutional experience from 2005 to 2009. Inclusion criteria were age > 18 y and discharge diagnosis of NSTI. We abstracted baseline demographics, physiology, laboratory values, and operative course from the medical record. The primary endpoint was in-hospital mortality; the secondary endpoint was extremity amputation rate. We compared baseline variables using Mann-Whitney, chi-square, and Fisher's exact test, as appropriate. Significance was set at P < 0.05.ResultsWe identified 80 cases over the study period. The cohort was 54% male (n = 43) and 53% white (n = 43), and had a mean age of 55 ± 16 y. There were no significant differences in demographics, physiology, or comorbidities between groups. In-hospital mortality was not different between groups (16% in the HBO group versus 19% in the non-HBO group; P = 0.77). In patients with extremity NSTI, the amputation rate did not differ significantly between patients who did not receive HBO and those who did (17% versus 25%; P = 0.46).ConclusionsHyperbaric oxygen therapy does not appear to decrease in-hospital mortality or amputation rate after in patients with NSTI. There may be a role for HBO in treatment of NSTI; nevertheless, consideration of HBO should never delay operative therapy. Further evidence of efficacy is necessary before HBO can be considered the standard of care in NSTI.     

TENS and acupuncture therapy for soft tissue pain

Acupuncture and transcutaneous electrical nerve stimulation (TENS) are two commonly used physical therapies in the management of soft tissue pain. Stimulation is used to provide analgesia in the treatment of both acute and chronic soft tissue pain.     

Spontaneous healing and wound contraction of soft tissue wounds of the hand

Wound contraction is efficient in healing certain soft tissue wounds of the hand. Such spontaneous healing has advantages over primary surgical wound closure, in being virtually free of haematoma and infection complications and in allowing early post-operative finger movements. This paper reviews experiences of this wound healing process in the healing of fingertip, dorsal and volar soft tissue defects.     

Effect of external pulsing electromagnetic fields on the healing of soft tissue

Since fibroblast behavior in bone healing can be altered electrically, it is plausible to hypothesize that fibroblast proliferation and function in soft tissue healing also would respond to an electromagnetically induced pulse. Reports of clinical impressions of accelerated closure of chronic skin wounds overlying areas being treated for nonunion have produced support for this hypothesis, but experimental data have been lacking. This study was designed to evaluate the effect of pulsed electromagnetic fields (PEMFs) with clinically employed wave-form parameters on the rate of closure of excisional wounds in normal animals and those with steroid retarded wound healing. Four groups, each containing 12 PEMF-treated rats and 12 control rats, were given different field exposures and two groups were treated with methylprednisolone. The wound areas were measured and tissue was harvested for histological examination at intervals for 28 days after wounding. There was no difference in the gross or microscopical appearance of wounds in each active group and its respective control group. Differences in the number of counted fibroblasts were not significant (p less than 0.5), and wound contraction and epithelialization proceeded at the same rate (t-test for equality of means, power = 90%). Electrical PEMF stimulation with the driving pulse used clinically for nonunion bony repair did not affect soft tissue healing in this model. No experimental support is provided for the reports of accelerated skin healing within therapeutic fields. It is possible that different wave-form characteristics are needed to provoke a response in soft tissue.     

Etiology, diagnosis and therapy of soft tissue infections

Soft tissue infections are caused by a multitude of bacteria. Their pathogenicity depends on the ability to adhere to surfaces, certain characteristics of the cell wall, exoenzymes or exotoxins, and endotoxins. Because etiologic classification of soft tissue infections is not satisfactory, we propose a clinical classification. 1. Abscesses are caused by staphylococci (carbuncle or suppurative hydroadenitis) or by polymicrobial infections (most subcutaneous abscesses). They are treated by incision and drainage and primary closure of the skin after drainage and curettage is often successful. Only in special cases are antibiotics indicated. 2. Cellulitis mostly caused by streptococci responds well to antibiotic therapy without surgery. 3. Ulcerative lesions i.e. pseudomonal gangrene and Meleney's gangrene need specific antibiotic therapy and complete excision with delayed grafting.     

Applying negative pressure therapy to deep pressure ulcers covered by soft necrotic tissue

Negative pressure therapy was applied to 39 deep pressure ulcers covered by soft necrotic tissue. All of the wounds were so deep that there were bones or ligaments just beneath the soft necrotic tissue. They had already received several types of conservative therapy including a necrotomy for periods ranging from 1 to 72 months. The wounds were minimally debrided and put in an adequately wet environment with negative pressure. This environment was established by the application of a suction‐dressing. All of these wounds showed clear wound beds within only 1 month. All of the wounds were successfully cured, either with or without a musculocutaneous flap. Negative pressure wound therapy is thus considered to be one of the choices for the management of non healing deep pressure ulcers covered by soft necrotic tissue.