Basics of cutaneous wound repair

BACKGROUND: Cutaneous wound repair consists of multiple integrated networks of cell-matrix-cytokine interactions. It is generally believed that a better understanding of these networks will lead to improved care of cutaneous wounds, whether freshly made by the surgeon's scalpel or previously existing and not healing secondary to underlying abnormalities. OBJECTIVE: This review is intended to update the readership in some of the salient aspects of wound repair networks. METHODS: To facilitate the review of multiple integrated networks, cutaneous wound repair was arbitrarily divided into three phases: inflammation, tissue regeneration including re-epithelialization and granulation tissue formation, and tissue reorganization. RESULTS: Throughout the entire process of wound repair it is clear that cells produce or alter various cytokines and extracellular matrix. The cytokines and matrix in turn alter the behavior of the producer cells (autocrine response) or neighbor cells (paracrine response). CONCLUSION: The dynamic reciprocity among cells, cytokines, and matrix material helps explain how integrated wound healing networks are sequential as well as tightly controlled.     

The application of deproteinized bovine bone mineral for ridge preservation prior to implantation. Clinical and histological observations in a case report

Alveolar ridge preservation following tooth extraction is important when implant-supported oral rehabilitation is considered. The ability to maintain the ridge allows implant placement in an ideal position, fulfilling both functional and esthetic demands. A deproteinized bovine bone mineral (DBBM) was used as a socket site filler material to maintain ridge configuration, without applying an occlusive membrane. The material was grafted and packed onto the socket sites immediately after extractions, and subsequently primary soft tissue closure was attempted. The ridge healed for 9 months before the second surgical procedure, in which the implant was placed. New bone formation was observed in all histological specimens. DBBM particles adhered to a highly osteocyte-rich woven and lamellar-type bone. Clinically and histologically, this report demonstrated DBBM particles to be an effective biocompatible filler agent in extraction sockets for ridge preservation prior to titanium fixture implantation. Randomized controlled clinical trials are needed to fully evaluate the usefulness of this material in ridge preservation after tooth extraction.     

Preservation of alveolar bone in extraction sockets using bioabsorbable membranes

The purpose of this study was to evaluate the clinical effectiveness of a bioabsorbable membrane made of glycolide and lactide polymers in preserving alveolar ridges following tooth extraction using a surgical technique based on the principles of guided bone regeneration. Sixteen patients requiring extractions of 2 anterior teeth or bicuspids participated in the study (split-mouth design). Following elevation of buccal and lingual full-thickness flaps and extraction of teeth, experimental sites were covered with bioabsorbable membranes; control sites did not receive any membrane. Titanium pins served as fixed reference points for measurements. Flaps were advanced in order to achieve primary closure of the surgical wound. No membrane became exposed in the course of healing. Reentry surgeries were performed at 6 months. Results showed that experimental sites presented with significantly less loss of alveolar bone height, more internal socket bone fill, and less horizontal resorption of the alveolar bone ridge. This study suggests that treatment of extraction sockets with membranes made of glycolide and lactide polymers is valuable in preserving alveolar bone in extraction sockets and preventing alveolar ridge defects.     

Diabetic periodontitis: possible lipid-induced defect in tissue repair through alteration of macrophage phenotype and function

BACKGROUND: Diabetes mellitus is a major health problem in the United States affecting approximately 13 million people. The five 'classic' complications which have historically been associated with the condition are microangiopathy, neuropathy, nephropathy, microvascular disease, and delayed wound healing. Recently, periodontal disease (PD) has been declared the 'sixth' major complication of diabetes as diabetics demonstrate an increased incidence and severity of PD. The cellular and molecular basis for diabetic PD is unknown. HYPOTHESIS: Recent evidence suggests that PD and delayed dermal wound healing may be manifestations of the same general systemic deficit in diabetes involving impairment of the cellular and molecular signal of wounding via alterations in macrophage phenotype. Diabetes-induced hyperlipidemia may interfere with the normal cellular and molecular signal of wounding by alteration of macrophage function and subsequent dysregulation of cytokines at the wound site. RESULTS: Preliminary data in both animal models and humans suggests that hyperglycemia, in combination with elevations of serum low density lipoproteins and triglycerides, leads to formation of advanced glycation end products (AGEs) which may alter macrophage phenotype. This may be responsible for dysregulation of macrophage cytokine production and increased inflammatory tissue destruction and alveolar bone loss. IMPLICATIONS: Future investigations will consider diabetic PD in the context of a generalized systemic wound healing deficit that manifests as PD in the face of constant pathologic wounding of the gingiva (bacterial plaque) or delayed dermal wound healing in instances of periodic traumatic wounding to other parts of the body. These types of studies will provide information concerning defective tissue repair in diabetics that will have clinical relevance for the understanding of PD and delayed dermal healing as well as applications of appropriate and specific therapies.     

A feasibility study evaluating rhBMP-2/absorbable collagen sponge device for local alveolar ridge preservation or augmentation

This two-center human clinical trial evaluated recombinant human bone morphogenetic protein-2 delivered in an absorbable collagen sponge (rhBMP-2/ACS) for either alveolar ridge preservation after tooth extraction or augmentation of localized osseous defects. This 24-month study comprised two parts: a 4-month acute safety and bone induction period (Part I) followed by a 20-month, osseointegration, functional restoration, and long-term safety evaluation (Part II). The primary objective of Part I, discussed in this article, was to evaluate the short-term safety and technical feasibility of the rhBMP-2 device implantation. Twelve patients (six preservation and six augmentation) were enrolled in the investigation. Patient safety was monitored by oral examinations, radiographs, and the collection of blood samples to measure serum chemistries, hematology, and potential antibody formation. Technical feasibility was evaluated by collecting information relating to the handling properties of the rhBMP-2/ACS device. The ability of various evaluative tools to measure the bone-inducing activity of the rhBMP-2/ACS device was also assessed. The clinical results suggested that rhBMP-2/ACS was well tolerated locally and systemically, with no serious adverse events. The device was found to be easily handled and adapted to the ridge and extraction socket. Using direct measurements, all sites demonstrated firmness and fullness to palpation at 4 weeks; however, a loss of volume was noted in some treatment areas between 4 and 8 weeks. Augmentation of the alveolar ridge was not observed in the patients as assessed by the evaluation techniques. This trial indicated that the use of rhBMP-2/ACS to preserve alveolar ridge after tooth extraction or augmentation of localized defects is safe and feasible. Bone fill was observed in all alveolar sockets filled with the rhBMP-2 device.     

Pseudobacteriuria associated with a urine flow rate transducer

Normal wound healing in skin embraces several reparative processes, many of which directly involve components of the extracellular matrix and the cutaneous basement membrane zone. Proteoglycans are a group of extracellular matrix macromolecules that have both structural and regulatory properties. In wound healing, certain proteoglycans fulfill a mechanical function of absorbing water and preventing tissue compression. However, proteoglycans may also have other roles in wound healing including a direct influence on inflammation, cell attachment and migration, and growth factor binding. Furthermore, proteoglycans may help to determine other aspects of the long-term quality of wound healing in skin through regulation of basement membrane permeability, epidermal hyperproliferation, and dermal fibrosis.     

Comparison of chromosomal damage induced by X-rays and Ar ions with an LET of 1840 keV/micrometer in G1 V79 cells

Wound healing in the adult is commonly compromised by excessive scar formation. In contrast, fetal wound healing is a regenerative process characterised by the conspicuous absence of scarring. Available evidence suggests that phenotypic differences between fetal and adult fibroblasts are important determinants of these distinct modes of tissue repair. In this context, a number of groups (including our own) have documented differences between fetal and adult fibroblasts with respect to such potentially relevant characteristics as migratory activity, motogenic response to cytokines and the synthesis of motility factors, cytokines and matrix macromolecules. The oral mucosa appears to be a privileged site in the adult in that it continues to display a fetal-like mode of wound healing. Data are presented in this review indicating that a subpopulation of gingival fibroblasts expresses several 'fetal-like' phenotypic characteristics. These observations are discussed in terms of both the continued expression of a fetal-like mode of wound healing in the oral mucosa and the possible differential involvement of distinct fibroblast subpopulations in the progression of periodontal disease.     

Corneal wound healing after laser in situ keratomileusis in rabbits

BACKGROUND: The aim of this study was to characterize the cell biology of wound healing in rabbit corneas subjected to laser in situ keratomileusis (LASIK). METHODS: Rabbit corneas underwent LASIK with various multizone photoablations or only a lamellar keratotomy followed by repositioning of the flap. We looked for indications for an active wound healing process. Immunohistochemistry for the extradomain A cellular fibronectin (EDA-cFn) or tenascin (Tn) and routine histology were examined. RESULTS: Four days after LASIK or lamellar keratotomy followed by repositioning of the flap, epithelial plugs and prominent keratocytes as well as Tn and EDA-cFn immunoreactions-indicative of a wound-healing process-appeared in the wound margins. Epithelial plugs were less conspicous, and prominent, presumably activated, keratocytes were no longer identified at the wound margin at 2.5 and 5 months after wounding. However, EDA-cFn and Tn immunoreactivities could still be observed. Only the stromal cells located in the periphery of the flap and in relatively close contact with the epithelium were surrounded by scar tissue expressing immunoreactivity for EDA-cFn or Tn. The central corneal stroma was devoid of scar tissue. CONCLUSION: Results indicate that the wound healing reaction after LASIK takes place only at the periphery of the microkeratome wound, leaving the central optical zone clear.     

Transforming growth factor-beta 3

Transforming Growth Factor-Beta (TGF-beta) is the general name for a family of naturally-occurring polypeptides which have multiple regulatory effects on cell proliferation and differentiation. Over the last decade it has become apparent that TGF-betas can be produced by most cell types and exert a wide range of effects in a context-dependent autocrine, paracrine or endocrine fashion via interactions with distinct receptors on the cell surface. This review summarizes current knowledge concerning the molecular and cellular biology of TGF-beta 3, the most recently described mammalian isoform, and focuses on those physiological actions which may lead to clinical applications, particularly in the indication areas of wound healing and chemoprotection.     

The extracted tooth pontic--provisional replacement during bone graft and implant healing

When tooth extraction is required, a provisional restoration may be utilized as an interim prosthesis during bone graft and implant healing. The selection of provisional replacement of the anterior teeth following extraction may have a direct influence on the success of the definitive tooth replacement. This article describes a technique for using the extracted tooth or a denture tooth as an interim prosthesis during bone graft and implant healing. This method of provisionalization offers several advantages, including no adjacent tooth preparation, natural appearance, and retention of the papillae.     

Dynamics of tissue changes found after mechanical loading of the rat incisor. II. A three-dimensional longitudinal study of the histopathologic aspects

The study comprised 60 lower left rat incisors subjected to 2 weeks of loading (19.7 +/- 1.6 gm) and 5 control teeth. After the loading period, 10 rats were killed with the springs in situ, and the remainder were killed in groups of 5 at intervals of 1 through 10 weeks after the springs were removed. The teeth were cross-sectioned serially (2 microns). The distance of each section from the apex and the time of its tissue formation in relation to load removal were calculated. Bone remodeling and dental and periodontal trauma were plotted according to their location on the tooth axis and circumference. Vigorous bone remodeling continued throughout the observation period, apposition and resorption sites intermingling around the tooth. Directionality, as expressed by the resorption/apposition ratio, for the formerly tensed and stressed areas was 0.61 +/- 0.07 and 1.79 +/- 0.52, respectively. However, in some of the groups directionality was negligible or reversed. New lesions of dentin (folding and resorption) were formed for 6 weeks after loading, whereas new damage to the enamel organ and enamel matrix appeared until week 9. The integrity of the PDL deteriorated for the first 8 weeks, as evidenced by edema, cell loss, scarring, and collagen fiber disorientation. Necrosis occurred throughout the recovery period. Fiber to bone attachment was disrupted by formation of big sinusoids adjacent to the bone. The frequency of most lesions decreased toward the end of the observation period. It is suggested that tissue recovery proceeds in subsiding cycles of tissue injury/tissue repair, a process that is much more prolonged than is generally believed.     

Reconstruction of residual alveolar cleft defects with one-stage mandibular bone grafts and osseointegrated implants

PURPOSE: This study evaluates a treatment regimen for reconstruction of residual maxillary alveolar cleft defects consisting of mandibular bone grafting and immediate implant installation. PATIENTS AND METHODS: Sixteen cleft patients (five female and 11 male) had residual cleft defects of the alveolar ridge reconstructed with bone grafts from the mandibular symphyseal region. The bone graft was pretapped at the donor site before fixation in the residual ridge with Br?nemark implants. Twenty implants were installed according to this concept. The period of observation ranged from 36 to 69 months, with a mean of 48 months after implant installation. RESULTS: Five patients developed wound dehiscenses that resulted in total or partial bone graft sequestration. Two implants were lost, one due to sequestration and the other due to mobility at the abutment procedure; 18 implants were still well functioning at the end of the observation period. However, all patients showed significant periimplant bone resorption after this one-stage treatment. CONCLUSION: Because of the observed complication rate, the one-stage procedure may not be optimal for reconstructing residual cleft defects.     

Evaluation of a western blot system (DAVIH-BLOT) for the confirmation of HIV-1 antibodies]

Matrix metalloproteinases (MMPs), a sort of important enzymes involved in extracellular matrix metabolism, play critical roles in the process of tissues remodeling, wound healing and metastasis of tumors. Dot blot and in situ hybridization were used in this study to detect the expression and localization of MMP-9, an important proteolytic enzyme implicated in bone resorption in bone tissues. The results showed that the level of MMP-9 mRNA expression in osteoporotic bone tissues was significantly higher than that in normal control group and the cell types that expressed MMP-9 mRNA included mono- and multi-nuclear osteoclasts and some lining cells on the surface of bone matrix. It was suggested that MMP-9 play a key role in the development of bone loss in osteoporosis.     

Helicobacter pylori and socioeconomic factors in Russia

Transforming growth factor beta 1 (TGF-beta 1) is a polyfunctional regulatory cytokine that has been shown to have roles in extracellular matrix interactions, soft tissue healing, and osteogenesis. Twenty-five microL of recombinant human TGF-beta 1 was added to guanidine-extracted demineralized bone matrix carrier and the implants were used to fill a 14-mm osteoperiosteal critical calvarial defect in New Zealand white rabbit model. The defects were allowed to heal over 4 weeks and the degree of new bone formation was assess by radiodensitometry and undecalcified bone histomorphometry techniques. Implants with TGF-beta 1 showed complete bridging of the gap with new bone in all cases, while the controls showed fibrous tissue repair of the gap with little or no new bone formation. These results demonstrate the ability of TGF-beta 1 to induce new bone in a brief time period in an inactive carrier.     

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in loose artificial hip joints

The role of extracellular matrix metalloproteinase enzymes and the tissue inhibitors of metalloproteinase in the periprostetic connective tissue matrix of loose artificial hip joints is reviewed. In the periprosthetic granulomatous interface connective tissues between bone and implants and inner cellular regenerating pseudocapsular tissues, matrix metalloproteinase 1, matrix metalloproteinase 2, matrix metalloproteinase 3, matrix metalloproteinase-9, and membrane type 1 matrix metalloproteinase enzymes can be shown in the light of immunohistochemistry, enzyme activity analysis, and messenger ribonucleic acid levels. Tissue inhibitors of metalloproteinase 1 and tissue inhibitors of metalloproteinase 2 also are found in the corresponding tissues. Analysis of matrix metalloproteinase and tissue inhibitors of metalloproteinase interaction shows imbalance between the enzymes and the endogenous inhibitors in favor of matrix metalloproteinase. This induces pathologic connective tissue remodeling in the interface and pseudocapsule. The data suggest that matrix metalloproteinase and tissue inhibitors of metalloproteinase system participate in the extracellular matrix degradation and tissue remodeling in artificial hip joints, and may contribute to the periprosthetic weakening, implant loosening, and osteolysis around implants. More evidence for their active involvement is sought by intervention studies with type specific matrix metalloproteinase inhibitors.     

Periodontal implications in implant treatment planning for aesthetic results

Insufficient hard and soft tissue height and width can be a repercussion of tooth loss or a result of postoperative healing following implant surgery. Insufficient bone can preclude proper implant positioning, while inadequately treated soft tissue will not exhibit a gingival appearance similar to that of the adjacent teeth. If hard and soft tissue discrepancies are not corrected by regenerative techniques, the replaced tooth appears long or overbulked gingivally. In order to create hard and soft tissue harmony, an understanding of the biological variables and periodontal implications is necessary.     

Electron microscopic observations on sperm penetration in cytochalasin-treated eggs of the rose bitterling

The influence of Aloe vera (L.) Burman f. on the glycosaminoglycan (GAG) components of the matrix in a healing wound was studied. Wound healing is a dynamic and complex sequence of events of which the major one is the synthesis of extracellular matrix components. The early stage of wound healing is characterized by the laying down of a provisional matrix, which is then followed by the formation of granulation tissue and synthesis of collagen and elastin. The provisional matrix or the ground substance consists of GAGs and proteoglycans (PGs), which are protein GAG conjugates. In the present work, we have studied the influence of Aloe vera on the content of GAG and its types in the granulation tissue of healing wounds. We have also reported the levels of a few enzymes involved in matrix metabolism. The amount of ground substance synthesized was found to be higher in the treated wounds, and in particular, hyaluronic acid and dermatan sulphate levels were increased. The levels of the reported glycohydrolases were elevated on treatment with Aloe vera, indicating increased turnover of the matrix. Both topical and oral treatments with Aloe vera were found to have a positive influence on the synthesis of GAGs and thereby beneficially modulate wound healing.     

Relative effects of wound healing and mechanical stimulus on early bone response to porous-coated implants

We hypothesized that early bone adaptation to well fixed porous-coated implants is influenced more by wound healing than by mechanical loading. To test this hypothesis, two groups of dogs with identical, hydraulically controlled porous-coated implants interference fit within distal femoral trabecular bone were used. One group had no load: the other had 35 N of load applied to the implants. At 5 weeks after surgery, the resulting adaptation of bone around the implants was quantified on a cellular basis by cytochemical analysis of type-I procollagen synthesis and on a structural basis using three-dimensional micro-computed tomography imaging. The percentage of trabecular surfaces covered by osteoblasts expressing type-I procollagen was significantly increased in bone surrounding the implant in both groups compared with contralateral control bone tissue. There was no difference between the groups with no load or 35 N of load. In addition, measures of trabecular bone structure did not differ significantly between the load and no-load groups. Taken together, these results suggest that wound healing plays a much greater role in the early response of bone to well fixed porous-coated implants than does mechanical stimulus.     

Lymphocyte function in wound healing and following injury

BACKGROUND: Injury activates a cascade of local and systemic immune responses. METHODS: A literature review was undertaken of lymphocyte function in wound healing and following injury. RESULTS: Lymphocytes are not required for the initiation of wound healing, but an intact cellular immune response is essential for a normal outcome of tissue repair. Injury affects lymphocyte immune mechanisms leading to generalized immunosuppression which, in turn, increases host susceptibility to infection and sepsis. Although the exact origin of post-traumatic immunosuppression remains unknown, stress hormones and immunosuppressive factors, such as inflammatory cytokines, prostaglandin E2 and nitric oxide, affect lymphocyte function adversely. Post-traumatic impairment of T lymphocyte immune function is reflected in decreased lymphocyte numbers, as well as altered T cell phenotype and activity. Antibody-producing B lymphocytes are variably affected by injury, probably secondary to alterations of T lymphocyte function, as a result of their close interaction with helper T cells. Therapeutic modulation of the host immune response may include non-specific and specific interventions to improve overall defence mechanisms. CONCLUSION: Early resuscitation to restore lymphocyte function after injury is important for tissue repair and the prevention of immunosuppression.     

Normoxic wound fluid contains high levels of vascular endothelial growth factor

OBJECTIVE: To examine the temporal integration of vascular endothelial growth factor (VEGF), which has been shown to be present in wound fluid, with the putatively related processes of wound fluid oxygen content, wound angiogenesis, and granulation tissue formation. SUMMARY BACKGROUND DATA: During cutaneous wound repair, new tissue formation starts with reepithelialization and is followed by granulation tissue formation, including neutrophil and macrophage accumulation, fibroblast ingrowth, matrix deposition, and angiogenesis. Because angiogenesis and increased vascular permeability are characteristic features of wound healing, VEGF may play an important role in tissue repair. METHODS: A ventral hernia, surgically created in the abdominal wall of female swine, was repaired using silicone sheeting and skin closure. Over time, a fluid-filled wound compartment formed, bounded by subcutaneous tissue and omentum. Ultrasonography was performed serially to examine the anatomy and dimensions of the subcutaneous tissue and wound compartment. Serial wound fluid samples, obtained by percutaneous aspiration, were analyzed for PO2, PCO2, pH, and growth factor concentrations. RESULTS: Three independent assays demonstrate that VEGF protein is present at substantially elevated levels in a wound fluid associated with the formation of abdominal granulation tissue. However, the wound fluid is not hypoxic at any time. Serial sampling reveals that transforming growth factor beta-1 protein appears in the wound fluid before VEGF. CONCLUSIONS: The results suggest that VEGF is a prominent regulator of wound angiogenesis and vessel permeability. A factor other than hypoxia, perhaps the earlier appearance of another growth factor, transforming growth factor beta-1, may positively regulate VEGF appearance in the wound fluid.