Development of a novel nonantigenic dermal implant composed of human placental collagen.

Injectable bovine collagen has proven to be safe and effective for the treatment of contour defects for more than 20 years. After intradermal exposure to bovine collagen, the most commonly reported side effect is hypersensitivity (incidence of approximately 3 percent to test and approximately 1 to 2 percent to subsequent treatment). The main purpose of this study was to evaluate tissue response and antibody production in bovine collagen-sensitive patients who were treated with human collagen (predominantly type I) implant.

Serological analysis of patients treated with a new surgical hemostat containing bovine proteins and autologous plasma.

A randomized, controlled clinical study of the management of diffuse bleeding with CoStasis surgical hemostat, a new hemostat containing bovine thrombin and collagen with the patient's own plasma, included patients undergoing cardiac, hepatic, iliac, and general surgery. Sera from 92 patients treated with CoStasis and 84 control patients were collected preoperatively and at a post surgical follow-up of 8 weeks. Among the control group, 57 patients were treated with Instat collagen sponge in noncardiac indications.

Efficacy of a novel hemostatic agent in animal models of impaired hemostasis.

This study evaluated the efficacy of a novel sprayable hemostat under both normal conditions and those of compromised coagulation. CoStasistrade mark Surgical Hemostat ("CoStasis"), containing collagen, thrombin, and autologous plasma, was compared to Instattrade mark collagen sponge, an investigational fibrin sealant, and a no treatment control, for the ability to control bleeding in a rabbit kidney model. Hemostatic performance was determined by time to hemostasis and blood loss in a nonsurvival, randomized, in vivo bleeding rabbit kidney model.

Evaluation of artecoll polymethylmethacrylate implant for soft-tissue augmentation: biocompatibility and chemical characterization.

Artecoll polymethylmethacrylate implant (Artecoll) is a combination of polymethylmethacrylate beads suspended in 3.5% atelocollagen and has been designed for use in soft-tissue augmentation applications. The biocompatibility and immunogenicity of Artecoll were evaluated to assess the safety of this product for use in the dermis.

Evaluation of antibody class in response to bovine collagen treatment in patients with urinary incontinence.

Purpose: Contigen Bard Collagen Implant (CI), made of highly purified bovine dermal type I collagen (BDC), is used as a bulking agent for the treatment of urinary stress incontinence. The humoral immune response to placement of this material in the urinary sphincter was evaluated.

Materials And Methods: In a prospective clinical study, patients were treated with CI in the urinary sphincter, and blood was collected at various timepoints following injection.

Immunohistochemical localization of intracellular and extracellular associated TGF beta in the skin of patients with systemic sclerosis (scleroderma) and primary Raynaud's phenomenon.

We have investigated the distribution of TGF beta using antibodies specific for its intracellular and extracellular forms in full-thickness biopsies of patients with SSc, primary Raynaud's phenomenon (PRP), systemic lupus erythematosus (SLE), and from normal subjects. Nine of 11 SSc biopsies demonstrated intracellular TGF beta in endothelial cells while only 6 exhibited extracellular TGF beta. Endothelial cells in skin biopsies of all PRP patients displayed both intracellular and extracellular TGF beta.

Clinical use of injectable bovine collagen: a decade of experience.

Bovine collagen has long been recognized as a safe, highly biocompatible material. In 1981 and 1985, two injectable fibrillar suspensions of purified bovine dermal collagen, Zyderm and Zyplast collagen implant, were commercially launched in the USA for use in soft tissue contour irregularities. Since that time more than 750 000 patients have been treated with Zyderm and/or Zyplast collagen implants internationally.

Immune responses to allogeneic and xenogeneic implants of collagen and collagen derivatives.

Whereas xenogeneic collagen has provided a safe and effective biomaterial for numerous medical applications, there are few instances in which data permit the correlation of the immunologic profile of well-defined devices with their clinical sequelae. A major exception is the use of injectable bovine dermal collagen for soft-tissue contour correction. The low incidence of hypersensitivity has been studied in the context of clinical efficacy and safety with several devices.

Adoptive transfer of tsk skin fibrosis to +/+ recipients by tsk bone marrow and spleen cells.

The tight skin mouse (Tsk/+) is an autosomal dominant example of inherited fibrosis whose pathogenesis is unclear. Autoimmune phenomena have been described previously. This study demonstrates the adoptive transfer of skin fibrosis to lethally irradiated syngeneic +/+ recipients by the transplantation of both bone marrow and spleen cells.

A retrospective study of antibodies against basement membrane antigens (type IV collagen and laminin) in patients with primary and secondary Raynaud's phenomenon.

Antibodies against type IV collagen were detected in the sera of 21% of patients with primary Raynaud's phenomenon (PRP) and 68% of patients with systemic sclerosis. Sera from 25% of the PRP patients and 48% of systemic sclerosis patients displayed antibodies to laminin. Eighty percent of the patients with PRP and antibodies to basement membrane antigens developed additional serologic or clinical manifestations, whereas only 16% of patients with PRP and no anti-basement membrane antibodies developed such manifestations.

Osteoinduction by implants of demineralized allogeneic bone matrix is diminished in vitamin D-deficient rats.

Experimental heterotopic bone formation was produced by subcutaneous implants of demineralized allogeneic bone matrix (DABM) in vitamin D-deficient (-D) animals that were either not treated or given vitamin D3 (+D) or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to determine the role of vitamin D and its most active metabolite in osteoinduction and implant remodeling. Histologically, implants in both +D and -D groups caused a similar acute inflammatory response, formation of a fibrous capsule, and chondrogenesis by 1 to 2 weeks after implantation. However, by 3 weeks after implantation implants in the -D animals had formed less bone matrix, had developed a defect in matrix mineralization, had reduced bone forming and bone resorbing surfaces, and had altered bone architecture resulting from defective bone remodeling.

Reaction to injectable collagen: results in animal models and clinical use.

Since its commercial release, Zyderm collagen implant has been used to treat more than 200,000 subjects in the United States for soft-tissue contour defects and more than 250,000 patients internationally (including the United States). Approximately 3 percent of subjects' skin tested with Zyderm collagen experience localized hypersensitivity reactions to collagen, whereas approximately 1 percent of treated patients demonstrate symptoms of hypersensitivity at treatment sites. Of the latter treatment responses reported since the conclusion of clinical trials with Zyderm, 56 percent occurred following the first treatment, 28 percent following the second, 10 percent following the third, and 6 percent following subsequent exposures.

Human monocyte modulation of endothelial cells and fibroblast growth: possible mechanism for fibrosis.

Several human diseases are characterized by vascular pathology, fibroblast activation, and excessive fibrosis (e.g., scleroderma, chronic graft versus host disease, pulmonary fibrosis).

The human immune response to reconstituted bovine collagen.

The human immune response to bovine dermal collagen was characterized through histologic, serologic, and immunoblotting methods. Collagen-sensitive patients were identified by hypersensitivity to intradermal exposure to ZYDERM Collagen Implant--a pepsin-solubilized, reconstituted, bovine dermal collagen. Biopsies of test sites in the forearm were obtained from several collagen-sensitive patients.

A comparative study of the biologic and immunologic response to medical devices derived from dermal collagen.

We examined collagen materials for soft tissue augmentation [Zyderm Collagen Implant (ZCI), glutaraldehyde cross-linked (GAX) collagen, and Koken Atelocollagen (Atelocollagen)]; hemostatic collagens [Gelfoam Gelatin Powder (Gelfoam), Avitene Microfibrillar Collagen Hemostat (Avitene), and Collastat Collagen Hemostat (Collastat)]; and reconstituted, intact fibrillar collagen from bovine skin in a subcutaneous guinea pig model. After 11, 25, and 39 days in situ, explants from animals injected with GAX collagen demonstrated greater wet-weight persistence than all other materials. Conversely, at all time points, the explants of Atelocollagen were the least persistent.

Mast cells and their degranulation in the Tsk mouse model of scleroderma.

The Tsk mouse is a genetically transmitted example of cutaneous fibrosis which has been compared with human scleroderma. During a systematic histopathological study of the Tsk mouse, both an increased number and an increased proportion of degranulated mast cells were observed. The consistent association of mast cells and fibrosis in scleroderma, graft-vs-host reactions (GVHR), and now the Tsk mouse raises the question of a pathogenetic role for mast cells in fibrotic disorders in general.

Cellular immunity to collagen and laminin in scleroderma.

Peripheral blood mononuclear cells (PBMC) obtained from scleroderma patients and normal controls were cultured in the presence of types I and IV collagen, intima collagen, laminin, and phytohemagglutinin. PBMC from 9 of 19 patients (47%) demonstrated lymphocyte transformation in response to laminin, and those from 2 of 17 patients (12%) demonstrated reactivity to type IV collagen. None of the patient PBMC were responsive to type I collagen or to intima collagen.

Comparison of inflammatory changes in established type II collagen- and adjuvant-induced arthritis using outbred Wistar rats.

Type II collagen- and adjuvant-induced arthritis in outbred Wistar rats were compared using parameters that measured the inflammatory response, cellular and humoral immunity, blood protein changes, drug metabolism and histopathological and bony changes of the inflamed paws. There was a lesser incidence (40-70%) and severity of collagen disease than the adjuvant model (incidence approximately 100%). The use of MDP increased the incidence and severity of collagen arthritis.

The absence of antibodies to type II collagen in established adjuvant arthritis in rats.

Utilizing an adjuvant arthritis model in rats, we examined humoral immunity to collagen and inflammation in animals with active disease and during drug therapy. Humoral immunity to types I or II collagen was not detected in the sera of rats with advanced adjuvant arthritis; this was in marked contrast to rats with type II collagen-induced arthritis which possessed serum antibodies to native and denatured type II collagen. Hind paw edema and bone pathology were monitored as parameters of inflammation.

Effect of gold salts, D-penicillamine and benoxaprofen on type II collagen-induced arthritis in rats.

We investigated the therapeutic effect of two gold salts, gold sodium thiomalate (GST, i.m.) and auranofin (p.

Delayed-type hypersensitivity to elastase-soluble lung peptides in the tight-skin (Tsk) mouse.

The development of immunity to homologous connective tissue antigens was studied with respect to aging in the tight-skin (Tsk) mouse mutant. A delayed-type hypersensitivity (DTH) response to elastase-solubilized lung peptides in Tsk/+ mice, which became evident at 10 weeks of age and increased in intensity until 22 weeks, was observed. Tsk mice did not demonstrate significant DTH responses when challenged with type I or IV collagen, and normal (+/+) littermates of all ages did not respond to any of the antigens under study.

Neutrophil response to LIF: lack of glucocorticoid effect despite enhanced chemokinesis.

Effects of glucocorticoids on human neutrophil responses to leukocyte migration inhibition factor (LIF) and neutrophil chemokinesis were examined using an agarose gel technique. The roles of endogenous monohydroxyeicosatetraenoic acids (HETE) and prostaglandins (PG) in basal neutrophil chemokinesis were also examined. Methylprednisolone sodium succinate (MPSS) in concentrations up to 200 micrograms/ml failed to inhibit the neutrophil response to LIF.

Cross-reactivity of cell-mediated immunity between interstitial (type I) and basement membrane (type IV) collagens.

In the present study, we demonstrate delayed-type hypersensitivity (DTH) to homologous type I collagen that cross-reacts with type IV collagen. Mice immunized with native or denatured type I collagens and challenged with these same antigens or native type IV collagen develop a peak DTH response on day 7. Challenge with denatured type IV collagen or collagenase-treated type IV collagen failed to elicit DTH in type I collagen-sensitized mice.

Antibodies to collagen in scleroderma.

Using the enzyme-linked immunosorbent assay (ELISA), we detected antibodies to interstitial (type I) and basement membrane (type IV) collagens in the sera of patients with scleroderma (systemic sclerosis). Antibodies against type IV collagen were found in significant levels in these patients and correlated with the presence of abnormal pulmonary diffusion capacity. Levels of antibodies to type I collagens also correlated significantly with pulmonary diffusion capacity.