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Henderson J.,Norwich University | Ferguson M.W.J.,Renovo Ltd | Terenghi G.,University of Manchester
Journal of Plastic, Reconstructive and Aesthetic Surgery | Year: 2012

Background: Wounds deprived of innervation fail to heal normally, and hypertrophic scars may be abnormally innervated. Manipulation of wounds alters the subsequent degree of scarring, and isoforms of transforming growth factor beta (TGFβ) are well established in this role, whilst TGFβ3 is undergoing clinical trials as an antiscarring agent for clinical use. It is unclear if treated wounds show changes in their innervation patterns as they mature into scars. Methods: Mice underwent 1cm 2 full thickness skin excisions which were treated with TGFβ1 or TGFβ3. Wounds were harvested between 5 and 84 days (n = 6 at each time point). Sections underwent histological scar assessment and immunohistochemical staining for protein gene product 9.5 (PGP9.5), a pan-neuronal marker, and the sensory neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP). Results: There was no difference in the reinnervation pattern between the peripheral and central parts of the wounds. Wounds treated with TGFβ3 healed with dermal collagen organised more like normal skin, whereas TGFβ1 treated wounds had abnormally orientated collagen within the scar compared to control treated wounds. Nerve fibre growth into the wounds followed a similar pattern in control and treated wounds, with only one significant difference during the healing process- at 42 days, the density of nerve fibres immunostained with PGP9.5 within the scar was greater than in control wounds. By 84 days, the density of PGP9.5, CGRP and SP immunopositive fibres were similar in control wounds and those treated with TGFβ isoforms. Conclusions: Changes in reinnervation patterns of wounds treated with TGFβ isoforms were only slightly different from those of control wounds, and by 84 days, the patterns were similar. © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.


Henderson J.,Addenbrookes Hospital | Ferguson M.W.J.,Renovo Ltd. | Terenghi G.,University of Manchester
Wound Repair and Regeneration | Year: 2011

Denervated wounds fail to heal normally, and hypertrophic scars are abnormally innervated. Wounds can be manipulated with cytokines to reduce subsequent scarring. Wounds treated with the antiscarring cytokine interleukin 10 (IL10) were investigated to assess if the treatment alterered patterns of reinnervation and revascularization as the wounds matured into scars. Thirty CD1 mice underwent intradermal injection of 100 μL phosphate-buffered saline (PBS) containing 125 ng IL10 or placebo at the margins of 1 cm2 full thickness dorsal skin excisions at the time of wounding and at 24 hours after wounding. Wounds were not dressed. Six IL10-treated and six control were harvested days 7, 14, 21, 42 and 84 postoperatively. Sections underwent histological scar assessment along with immunohistochemical staining for protein gene product 9.5 (PGP9.5), a pan-neuronal marker, and the sensory neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP). The endothelial marker von Willebrand factor (VWF) was used to allow co-localization and quantification of blood vessels. Quantitative analysis was performed on the periphery and center of wounds. Wounds treated with IL10 healed with dermal collagen organized into a pattern more closely resembling normal skin than control wounds. IL10 changed the pattern of CGRP reinnervation during the healing process, but at 84 days, the density levels of all nerve fiber types were similar to controls. Wounds treated with IL10 were more vascular than untreated wounds during healing, but by 84 days, VWF density was that of unwounded skin. © 2011 by the Wound Healing Society.


BACKGROUND:: The authors report on a prospective, randomized, placebo-controlled phase II trial to investigate avotermin (transforming growth factor beta-3) for reducing scarring resulting from acute incised skin wounds. METHODS:: Seventy-one healthy male subjects (18 to 45 years) received avotermin at 50 or 200 ng/100 μl/linear centimeter of wound margin. Subjects received three standardized 1-cm incisional wounds on the inner aspect of each upper arm. Wounds were randomized to receive (into each margin): no injection (standard wound care only), one intradermal injection of avotermin or placebo (immediately before surgery), or two injections of avotermin or placebo (immediately before surgery and 24 hours later). The primary efficacy variable was a 10-cm visual analog scale score, which assessed how closely scars resembled normal skin, administered at month 12 by an independent external scar assessment panel (a panel of lay public individuals). RESULTS:: Avotermin at 200 ng/100 μl/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (p < 0.02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (p = 0.043). Treatment was well tolerated. CONCLUSION:: These results confirm that avotermin is the first of a new class of regenerative medicines that reduce scarring when administered once or twice to the approximated margins of acute skin incisions. © 2010 by the American Society of Plastic Surgeons.


Patent
RENOVO Ltd | Date: 2010-06-10

There is provided the use of mannose-6-phosphate, or a salt, precursor or analogue thereof, for providing and/or maintaining a consistent skin colour, particularly to reducing redness of skin. There is also provided the use of mannose-6-phosphate, or a salt, precursor or analogue thereof, as a skin improvement agent for providing a cosmetic effect and mannose-6-phosphate, or a salt, precursor or analogue thereof, for use in treating normal or damaged skin, wherein damaged skin is skin that has been subject to epidermal and/or dermal damage.


Patent
Renovo Ltd | Date: 2011-06-15

The invention relates to a peptide, or derivative thereof, according to the formula X_(1)X_(2),-X_(3)- Thr-X_(4)-Lys-X_(5)-Arg-X_(6). (SEQ ID No. 1), wherein:X_(1) is Ala or GlyX_(2) is Tyr or PheX_(3), X_(4) and X_(5) are independently selected from the group comprising Met, Ile, Leu and Val; andX_(6) is selected from the group comprising Asp, Gln; Glu and Asn;for use in promoting accelerated wound healing with reduced scarring. The invention also relates to a DNA molecule encoding the peptide according to SEQ ID NO:1 for use in promoting accelerated wound healing with reduced scarring, said DNA molecule being capable of being transcribed to lead to expression of the peptide.


There is provided the use of monomeric TGF-s, or there fragments or derivatives, as medicaments. These medicaments preferably comprise monomeric TGF-3, or fragments or derivatives thereof. The medicaments provided may be used in the acceleration of wounding and/or the inhibition of scarring, in the promotion of epithelial regeneration, or in the prevention and/or treatment of fibrotic disorders.


Patent
RENOVO Ltd | Date: 2011-10-07

The present invention relates to the use of a peptide, or derivative thereof of general formula X1-X2-X3-ThT-X4-LyS-X5-ATg-X6 for promoting accelerated wound healing with reduced scarring. X1 is Ala or Gly; X2 is Tyr or Phe; X3, X4 and X5 are independently selected from the group comprising Met, He, Leu and Val; and X6 is selected from the group comprising Asp, Gln and Glu.


Patent
Renovo Ltd | Date: 2011-03-23

There is provided an agent having TGF-_(3) activity for use in the promotion of epithelial regeneration. Suitable agents may be selected from the group consisting of TGF-_(3), a fragment, derivative or variant of TGF-_(3), a substance able to promote and/or mimic the biological activity of TGF-_(3). The agents may be used in a formulation that further comprises a sugar, such as a sugar selected from the group consisting of: monosaccharides and disaccharides, such as maltose, mannose, sucrose, glucose, or trehalose. Also provided are methods of preparing therapeutic formulations suitable for localised parenteral administration, for use in the promotion of epithelial regeneration; agents having TGF-_(3) activity for use preparing an epithelial graft donor site for re-harvesting; and delivery systems for use in gene therapy techniques.


Patent
Renovo Ltd | Date: 2011-01-11

The invention provides TGF-3s, or fragments or derivatives thereof, wherein the alpha-helix-forming domain between amino acid residues (58) and (67) of full-length wild type TGF-3 comprises at least one alpha-helix-stabilising substitution. The invention also provides TGF-3s, or fragments or derivatives thereof, wherein the Glycine residue at position (63) of full-length wild type TGF-3 is replaced with Proline. Further still, the invention provides TGF-3s, or fragments or derivatives thereof, comprising a substitution of the Glutamic acid residue at position (12) of full-length wild type TGF-3 and/or the Arginine residue at position (52) of full-length wild type TGF-3. The invention also provides medicaments and methods of treatment using such TGF-3s.


Trademark
Renovo Corporation | Date: 2013-01-15

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