Biomedical subjects

Kathleen E Rodgers

Publications and source records attributed to Kathleen E Rodgers.

10 recordsLinked to original sources

PubMed2007

A modern biomaterial for adhesion prevention.

A biomaterial composed of carboxymethylcellulose, poly(ethylene oxide), and calcium can be prepared in a variety of ways to reduce fibrin deposition and adhesion formation. This biomaterial platform can be formulated into a flowable gel with tissue adherence appropriate for use in minimally invasive surgery. The device remains at the site of placement even in gravitationally dependent areas. A peridural formulation was shown in preclinical studies to be safe and effective in reducing adhesions to dura following spinal surgery. A peritoneal formulation used on pelvic organs following peritoneal cavity surgery was also shown to be safe and effective. A clinical feasibility study showed that patients with severe back pain and lower extremity weakness treated with the peridural formulation, applied over their nerve roots following laminectomy or laminotomy, experienced significantly reduced symptoms when compared with surgery-only controls. The peritoneal formulation was shown in two multicenter feasibility studies of women undergoing pelvic surgery to significantly reduce adhesion formation when compared with surgery-only controls. Confirmation of the feasibility studies awaits results from pivotal clinical trials. These formulations were safe, effective, and easy to use. This biomaterial provided a benefit to patients undergoing surgery where postsurgical adhesion formation is a concern.

Animals↗

PubMed2005

Phase I/II dose escalation study of angiotensin 1-7 [A(1-7)] administered before and after chemotherapy in patients with newly diagnosed breast cancer.

PURPOSE: Multilineage cytopenias occur following myelosuppressive chemotherapy. Most hematopoietic agents differentiate along a single lineage and fail to prevent progressive cytopenias. Angiotensin 1-7 [A(1-7)] is a hematopoietic agent that stimulates the proliferation of multipotential and differentiated progenitor cells in cultured bone marrow and human cord blood. The purpose of this study was to determine the optimal biologic dose and the maximum tolerated dose of A(1-7). EXPERIMENTAL DESIGN: This study determined the safety and activity of A(1-7) following chemotherapy in patients with breast cancer. Toxicity was assessed by administering A(1-7) daily for 7 days followed by a 7-day washout prior to the first cycle of chemotherapy. Beginning 2 days after chemotherapy and continuing daily for at least 10 days, fifteen patients received five different A(1-7) doses and five patients received filgrastim as a comparator group over three cycles of chemotherapy. RESULTS: No dose-limiting toxicity was observed following A(1-7). The frequency of adverse events was slightly lower in A(1-7) than in filgrastim patients. No patient required a chemotherapy modification due to hematologic toxicity. There was an apparent differential dose-response sensitivity of the various lineages to A(1-7). At a dose of 100 microg/kg, A(1-7) reduced the frequency of grade 2-4 thrombocytopenia, anemia, and grade 3-4 lymphopenia as compared to filgrastim. CONCLUSION: These data suggest that A(1-7) may be beneficial in attenuating multilineage cytopenias following chemotherapy at a dose of 100 mug/kg per day.

Adult↗

PubMed2005

Technology evaluation: Chrysalin (Orthologic).

OrthoLogic (formerly Chrysalis) is developing Chrysalin, a synthetic 23-amino acid peptide that mimics a portion of human thrombin. The compound is in phase II clinical trials for the potential treatment of diabetic foot ulcers and phase III trials for cartilage repair and bone fractures.

Animals↗

PubMed2003

Synergistic effects of co-administration of angiotensin 1-7 and Neupogen on hematopoietic recovery in mice.

PURPOSE: Angiotensin 1-7 [A(1-7)] is a seven amino acid peptide that has been shown to increase the proliferation of epidermal stem cells after dermal injury and the number of hematopoietic progenitors in the bone marrow of myelosuppressed mice. In this study, the effect of combining A(1-7) with Neupogen on hematopoietic recovery and bone marrow progenitors was evaluated. MATERIALS AND METHODS: Intravenous 5-fluorouracil (5FU) was administered to induce myelosuppression. Administration of A(1-7) and/or Neupogen was initiated 2 days after chemotherapy. Angiotensin II (AII) and A(1-7) binding were assessed by flow cytometric analysis. Hematopoietic progenitors were counted by colony forming assays. Recovery of formed elements in the blood was evaluated by hemocytometer. RESULTS: Flow cytometric analysis indicated that the number of early hematopoietic progenitors (Lin(-)Sca1(+)cKit(+)) that bind AII or A(1-7) increased 5-7 days after intravenous injection of 150 mg/kg 5FU. Further, administration of A(1-7) led to a slight increase in the number of circulating leukocytes and platelets after this chemotherapeutic regimen. When given in combination with a subclinical dose of Neupogen, a synergistic effect on the number of circulating leukocytes was observed, but there was no further effect on the number of circulating platelets. In myelosuppressed mice, A(1-7) had its most profound effect on the number of hematopoietic progenitors in the bone marrow. The progenitors evaluated in the study included BFU-E, CFU-Meg, CFU-GM and CFU-GEMM. There was an increase in the number of these progenitors in the bone marrow, indicating an effect on all hematopoietic lineages. When given in combination with Neupogen, these effects were synergistic for the numbers of BFU-E and CFU-Meg (Neupogen by itself had no effect) and for the myeloid progenitors at lower doses of A(1-7). CONCLUSIONS: These results suggest that these hematopoietic agents act at different sites within the hematopoietic cascade and that combining these two agents may be of benefit in the treatment of hematopoietic disorders.

Angiotensin I↗

PubMed2003

Acceleration of healing, reduction of fibrotic scar, and normalization of tissue architecture by an angiotensin analogue, NorLeu3-A(1-7).

Angiotensin peptides have been demonstrated to modulate cellular proliferation, angiogenesis, and dermal repair. In this report, the effects of an analogue of the active angiotensin peptide angiotensin(1-7), namely norLeu3-angiotensin(1-7) (NorLeu3-A(1-7)), on the healing of epithelial wounds are presented. Three models were used to evaluate the normal (rats) and delayed (diabetic mice) healing responses of full-thickness excision wounds and the healing responses of full-thickness incision wounds (rats). NorLeu3-A(1-7) was superior to the naturally occurring angiotensin peptide angiotensin(1-7) and to Regranex (Ortho McNeil, Somerville, N.J.) (a formulation of recombinant platelet-derived growth factor used clinically for the treatment of diabetic ulcers) in accelerating tissue repair. By day 9 (normal rats) and day 11 (diabetic mice), the differences in the rates of closure of full-thickness excision wounds between NorLeu3-A(1-7) and Regranex were statistically significant (n = 5 per group). Full healing was observed for 60 percent of the diabetic mice treated topically with NorLeu3-A(1-7) by day 18 after injury, at which time full healing of wounds on placebo-treated or Regranex-treated diabetic mice was not observed. In the rat incision model, accelerated healing and reduced gross appearance of scarification were observed. Administration of NorLeu3-A(1-7) reduced fibrosis and scarring in the healing wounds. This action was more pronounced with longer administration of the peptide after injury. In fact, if systemic administration of the peptide (NorLeu3-A(1-7)) was continued during the remodeling phase, then the formation of new adnexal structures at the center of full-thickness excision wounds was observed, with an increase in the appearance of small immature hair follicles at the sites of the excision wounds. The action of this peptide was blocked by the AT receptor antagonist d-Ala7-angiotensin(1-7), which suggests that this receptor is involved in the healing responses to exogenous NorLeu3-A(1-7). These data suggest that this novel angiotensin peptide has the potential to be of benefit in accelerating wound repair and reducing scar formation.

Angiotensin I↗

PubMed2003

Histological evaluation of the effects of angiotensin peptides on wound repair in diabetic mice.

Recent studies have shown that angiotensin peptides accelerate dermal repair. Histological observation of samples taken at the termination of studies showed that the wounds treated with peptides were mature and organized by day 25 after full thickness excision in diabetic mice. However, the mechanisms by which this acceleration occurs has not been determined. In the experiments described here, the effect of angiotensin peptides (AII, A(1-7) and NorLeu (3)-A(1-7) on the quality of the healing wound was evaluated histologically. Administration of the peptides accelerated collagen deposition, re-epithelialization and new blood vessels formation. By day 4, the percentage of the wound with collagen increased two- to six-fold depending upon the peptide. The increase by angiotensin peptides continued throughout the experimental period. On days 4 and 7 9 (only) after injury, exposure to angiotensin peptides increased the number of blood vessels at wound site two-to three-fold. Finally, the percentage of the wound site covered with new epithelium increased after administration of angiotensin peptides. Re-epithelialization was observed as early as day 4 in wounds treated ith angiotensin peptides. The increase was greater at later time points (up to 8-fold ar day 14 with NorLeu(3)-A(1-7) had an increase in neutrophils and macrophages on day 4 after wounding. Overall, administration of these peptides resulted in a healing site that was more mature, including reorganization of the collagen into a basket-weave appearance. Further, these studies confirm the superiority of NorLeu(3)-A(1-7) to AII and A(1-7) in wound healing evaluated at a microscopic level.

Angiotensins↗

PubMed2002

Accelerated recovery from irradiation injury by angiotensin peptides.

PURPOSE: Angiotensin peptides have been shown to affect the proliferation and chemotaxis of multiple cell types. More recent studies in this laboratory have shown that angiotensin II (AII) can increase colony formation and proliferation by hematopoietic progenitors and mesenchymal cells in vitro. As white blood cell (WBC) recovery after bone marrow injury requires progenitor proliferation, the effect of AII and angiotensin (1-7) [A(1-7)], a non-hypertensive fragment of AII, on recovery from total body irradiation was evaluated in C57Bl/6 mice. MATERIALS AND METHODS: The effect of angiotensin peptides on hematopoietic recovery and the number of progenitors in the bone marrow of irradiated C57Bl/6 mice was evaluated. RESULTS: Treatment of animals with angiotensin peptides accelerated hematopoietic recovery and increased the number of hematopoietic progenitors in bone marrow and in the blood. The increase in WBC concentration continued for a longer time after cessation of AII therapy than after treatment with filgrastim. Specifically, the number of WBCs continued to increase 21 days after irradiation with 7 days of angiotensin peptide administration. In contrast, the number of WBCs increased through day 13 with 7 days of filgrastim administration. On day 35 after irradiation (28 days after the last treatment), AII was shown to have increased the number of CFU-GM in the bone marrow of irradiated mice, whereas filgrastim administration had not. Angiotensin peptides also reduced the drop in platelet concentration after irradiation and increased the number of megakaryocyte precursors and megakaryocytes in the bone marrow. Receptor blocking studies indicated that losartan, an antagonist of the angiotensin type 1 receptor, blocked recovery of WBC levels in response to treatment with AII. In contrast, the increase in WBC levels in response to treatment with A(1-7), a ligand for other angiotensin receptors, was not affected by losartan. CONCLUSIONS: These findings suggest that these peptides utilize distinct receptors in the stimulation of hematopoietic recovery. In summary, systemic administration of angiotensin peptides led to an acceleration in hematopoietic recovery after irradiation. These peptides act to stimulate the formation of bone marrow progenitors, thereby facilitating recovery after myelosuppressive irradiation.

Angiotensin I↗

PubMedDate not supplied

Reduction of epidural fibrosis in lumbar surgery with Oxiplex adhesion barriers of carboxymethylcellulose and polyethylene oxide.

BACKGROUND CONTEXT: Postsurgical epidural adhesions and fibrosis after surgery for lumbar disc herniation are a consequence of normal wound healing. The presence of fibrosis renders reoperations risky, and in some patients fibrosis may lead to nerve root tethering. PURPOSE: One approach to minimizing the risk of developing epidural adhesions is to provide a barrier between the dural membrane and the healing connective tissues. The purpose of these studies was to evaluate such a barrier device. STUDY DESIGN/SETTING: In vivo investigation in an animal model at a university laboratory. PATIENT SAMPLE: Rabbit. OUTCOME MEASURES: Gross and histomorphic evaluation. METHODS: Barriers comprised of carboxymethylcellulose (CMC) and polyethylene oxide (PEO) (Oxiplex; FzioMed, Inc., San Luis Obispo, CA) were studied as devices to reduce epidural adhesion formation in rabbit laminotomy and laminectomy models. The barriers tested were either a gel alone (gel) or a gel covered with a film (gel/film combination). Two laminotomy or laminectomy sites (depending on the surgical method) were created in each rabbit at L4 and L6. One site was treated with a CMC/PEO gel, or CMC/PEO gel/film combination, and the other site served as a surgical control. Two surgical models that differed in the extent of adhesion formation at untreated injury sites and the method of injury generation were used. RESULTS: Model A, which did not incorporate dural abrasion, resulted in up to 40% adhesion-free laminectomy sites in controls. Model B, which did incorporate abrasion of the dural membrane, resulted in less than 10% adhesion-free laminotomy sites in controls. Compositions of CMC/PEO gels (2.5% to 10% PEO) and films (22.5% PEO) were tested in both models. Efficacy parameters included measuring the number of sites free of epidural fibrosis and reduction in the severity of fibrosis (adhesions). Both gels and gel/film combinations consistently reduced the frequency and the extent of epidural fibrosis in both models. Gels of CMC/PEO containing a higher content of PEO (10%) and a higher molecular weight of PEO (4.4 mD) were most effective in Model B and resulted in up to 84% laminotomy sites with minimal or no epidural fibrosis, whereas controls exhibited over 90% of the sites with epidural fibrosis. Histological evaluation of the surgical sites indicated that the reduction of epidural fibrosis was accompanied by normal bone healing. In addition, these experiments demonstrated that the gel/film combination provided no additional benefit to that obtained by the gel alone. CONCLUSIONS: Gels of CMC/PEO reduced epidural fibrosis and did not impair normal heal ing.

Animals↗

PubMedDate not supplied

Effect of NorLeu3-A(1-7) on scar formation over time after full-thickness incision injury in the rat.

Previous studies have shown that the angiotensin peptide NorLeu3-A(1-7) accelerates dermal healing and reduces scar formation. In this report, the effect of this peptide on scar formation is more fully delineated. The effect of surgical day, time after injury, and observer on the clinical appearance of the incision were determined. Clinical observations of incision site, including inflammation, opening of the injury, and appearance of scar, were conducted by two observers blinded to treatment (two observations per time point) twice weekly. Opening of the incision occurred in 35-40% of incisions early (days 4 and 7) after injury. Administration of NorLeu3-A(1-7) at the time of injury reduced the incidence of opening at day 7 to approximately 20%. Further, the length of the wound opening was significantly reduced in the peptide-treated incisions at day 7. Starting on day 14 after injury, scar formation was evaluated. Up to 80-90% of control animals had observable scars starting on day 14. Thereafter, the scar remodeled with fewer incisions having visible scar on day 28. With administration of NorLeu3-A(1-7), significantly fewer incisions had observable scars starting on day 14 and throughout the study. As few as 20% of the incisions had observable scars on day 28. The histological appearance of the healing wound was also evaluated at weekly intervals starting on day 7 and continued until day 42. At day 7, the maximal number of fibroblasts at the wound site was observed. Thereafter, the number gradually reduced, reaching a plateau at day 28. The administration of peptide had no effect on fibroblast number at the incision site. A similar pattern was observed in the thickness of the epidermis with the resolution of the hyperplastic phase at day 21. Administration of the peptide significantly increased epidermal height at day 7. Blood vessel formation peaked on day 21 and 28 in control wounds and was further enhanced by peptide administration during the neovascularization phase. After day 28, blood vessel number was comparable between control and treated incisions. Collagen deposition and remodeling were increased by the administration of NorLeu3-A(1-7) at the time of injury.

Angiotensin II↗

PubMedDate not supplied

Expression of intracellular filament, collagen, and collagenase genes in diabetic and normal skin after injury.

Reports have shown differences in gene expression in the skin of diabetic and normal mice both at baseline and after injury. Cluster analysis identified distinct expression patterns within intermediate filaments and extracellular proteins. This report addresses the effect of diabetes and injury on the expression of keratin-associated proteins, keratin complexes, procollagen, and collagenase (matrix metalloproteinase; MMP) genes. At baseline keratin-associated proteins and keratin complexes gene expression was increased in diabetic mice. After surgery, the level of expression for keratin-associated proteins and keratin complexes genes decreased in diabetic mice, but did not change in normal mice. If the expression of a procollagen gene differed between diabetic and normal mice, the expression was lower in diabetic mice. Procollagen gene expression was elevated after skin excision compared with noninjured skin. At baseline, the level of MMP and tissue inhibitor of metalloproteinase gene expression was comparable between mouse strains. With injury, the expression of several MMP genes was increased in both mouse strains, but to higher levels in diabetic mice. At day 7, the level of MMP-9 activity in granulation tissue was elevated. This alteration may contribute to delayed healing in diabetic mice. Therefore, differences in gene expression exist between mouse strains and can assist in understanding of physiological manifestations, including delayed healing, in diabetic mice.

Animals↗