WO2006123226A2

WO2006123226A2 - An inhibitor of mtor for inhibiting the formation of scar tissue

Info

Publication number: WO2006123226A2
Application number: PCT/IB2006/001300
Authority: WO
Inventors: Hugo Barrie Nel
Original assignee: Individual
Current assignee: Individual
Priority date: 2005-05-18
Filing date: 2006-05-18
Publication date: 2006-11-23
Anticipated expiration: 2007-11-18
Also published as: WO2006123226A3

Abstract

The invention describes the use of an inhibitor of the mammalian Target of Rapamycin (mTOR), such as sirolimus or everolimus, to effect a clinical response on an insult or wound. The compound can be administered in any suitable local or topical delivery form, such as by local injection; local delivery systems, for example impregnated implants and slow release devices; forms of dressings, impregnated suturing material; impregnated mesh, sheets, membranes, prosthetics; gels containing the compound; and so forth. Typical applications where it would be useful to prevent scarring by inhibiting the mTOR according to the invention are: cosmetic surgery; scar revision surgery, including excision of scars and contracture release; tendon repair; nerve repair; and fibrotic or inflammatory conditions, such as de Quervain's disease, Peyronie's disease, plantar fasciitis, Dupuytren's disease, finger triggering, forms of synovitis, such as rheumatoid arthritis, after laparotomy to prevent adhesions, after brain surgery to prevent gliosis, and microsurgery, such as microvascular surgery and fallopian tube surgery.

Description

A METHOD OF INHIBITING THE FORMATION OF SCAR TISSUE

BACKGROUND OF THE INVENTION

The invention relates to a method for preventing and/or treating acute inflammation and fibrosis during wound healing so as to inhibit the formation of scar tissue.

The wound (or insult) may be a result of trauma, surgery or a disease process. Invariably, such an insult leads to acute inflammation, which in turn leads to a more chronic process of fibrosis, scarring and remodeling. Fibrosis is the common denominator in the healing of almost all tissues. Examples are unsightly dermal scars (the fibrous tissue replacing normal tissues destroyed by injury or disease), contractures from scarring, stiffness around joints, immobility of injured or operated tendons, fibrosis after abdominal surgery, gliosis following brain surgery, and so forth. Fibrosis also interferes with optimal healing or function, and it would therefore be beneficial to be able to prevent or treat the occurrence thereof.

An elaboration upon one example is that of a tendon laceration. If a patient were to acquire a tendon laceration over the palmar aspect of a finger, for example from a knife cut, the wounded finger would be unable to flex. Surgery would need to be performed to reunite the tendon. After surgery, the need to immobilize the tendon for a period long enough so as to allow complete healing needs to be balanced with the need to mobilize the tendon early enough so as to prevent fibrosis around it, and thereby prevent a stiff joint from forming. Thus, the finger would usually be immobilized for two to three weeks after surgery, after which hand therapy would be commenced. Complications which could occur include rupture of the tendon repair or scarring around the tendon, both of which require further surgery.

The applicant has therefore identified a need for a method of preventing and/or treating acute inflammation during the healing process, thereby preventing unwanted fibrosis and scarring. SUMMARY OF THE INVENTION

According to a first embodiment of the invention, there is provided a method of inhibiting the formation of scar tissue during wound healing, the method including the step of administering to a patient in need thereof a compound which inhibits the mammalian Target of Rapamycin (mTOR).

The compound may be sirolimus or a derivative or pharmaceutically acceptable salt thereof, such as everolimus.

The wound may be from an insult to the patient, such as surgery or an injury, or may be a result of a disease process.

The compound may be administered alone or in combination with one or more other pharmaceutical compounds. The compound may be administered to the patient prior to, during and/or after the infliction of the wound.

The administration of the compound may result in one or more of the following responses: control of the T-cell proliferation cascade; control of acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring; and quicker healing.

According to a second embodiment of the invention, there is provided a method of inhibiting the development of insult-related fibrosis in a patient, the method including the step of administering to the patient a compound which inhibits the mammalian Target of Rapamycin (mTOR).

According to a third embodiment of the invention, there is provided a method of suppressing inflammation in response to an insult, the method including the step of administering to a patient in need thereof a compound which inhibits the mammalian Target of Rapamycin (mTOR). The compound may be sirolimus or a derivative or pharmaceutically acceptable salt thereof, such as everolimus.

According to a fourth embodiment of the invention, there is provided the use of a compound which inhibits the mammalian Target of Rapamycin (mTOR) in a method of manufacturing a medicament for use in a method of inhibiting the development of insult-related fibrosis, suppressing inflammation in response to an insult and/or inhibiting the formation of scar tissue during wound healing.

According to a fifth embodiment of the invention, there is provided a compound which inhibits the mammalian Target of Rapamycin (mTOR) for use in a method of inhibiting the development of insult-related fibrosis, suppressing inflammation in response to an insult and/or inhibiting the formation of scar tissue during wound healing.

According to a sixth embodiment of the invention, there is provided an article of manufacture for inhibiting the development of insult-related fibrosis, suppressing inflammation in response to an insult and/or inhibiting the formation of scar tissue during wound healing, the article including a compound which inhibits the mammalian Target of Rapamycin (mTOR).

The article may be a surgical implant, a medical garment, a medical dressing, such as a bandage or plaster, medical staples, suture material, mesh, sheets, membranes, prosthetics, and the like.

The article may include a delayed release formulation of the compound, thereby allowing the compound to be administered to a patient over a period of time. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 48h Control haematoxylin and eosin staining (H&E) - one half of dehisced wound;

Figure 2 48h Control H&E (higher magnification) - neutrophil infiltration in wound edge;

Figure 3 48h Control Silver - Wound edge with area of proteolysis and debris;

Figure 4 48h Test H&E - One half of dehisced wound;

Figure 5 48h Test H&E - No neutrophil infiltration;

Figure 6a 48h Test Silver - No proteolytic activity;

Figure 6b Day 5 Control H&E (low magnification) - Fibroblast proliferation;

Figure 7 Day 5 Control Silver - Thickened epidermis and early scar;

Figure 8 Day 5 Control Silver (higher magnification)- Irregular collagen;

Figure 9 Day 5 Control H&E - Early scar with fibroblasts and thickened epidermis;

Figure 10 Day 5 Control Silver - Thickened epidermis and irregular collagen formation;

Figure 11 Day 5 Test H&E (low magnification) - Epidermal contour notch, thickened epidermis, no dermal scar; Figure 12 Day 5 Test Silver - Epidermal contour irregularity with thickened epidermis, no scar;

Figure 13 Day 5 Silver (higher magnification) - Normal dermal collagen architecture; Figure 14 Day 5 Test H&E - Interruption in epidermal contour, no scar; Figure 15 Day 5 Test Silver - Normal dermal collagen; Figure 16 Day 5 Test India Ink H&E - Fibrotic reaction in dermis, with lymphatic clearance of charcoal (India ink) particles; Figure 17 Day 5 Test India Ink Silver (higher magnification) - abnormal collagen with charcoal particles being cleared.

DETAILED DESCRIPTION OF THE INVENTION

The use of an inhibitor of the mammalian Target of Rapamycin (mTOR) to effect a clinical response on an insult or wound is described herein.

The applicant has surprisingly found that an mTOR inhibiting compound, sirolimus, can significantly reduce the formation of scar tissue during wound healing. It is envisaged that other pharmaceutically acceptable mTOR inhibitors, such as everolimus, would also have the same effect. The compound can be administered to a patient orally or parenterally before, during or after a surgical procedure, or after an insult. The compound can be administered in any suitable local or topical delivery form, such as by local injection; local delivery systems, for example impregnated implants and slow release devices; forms of dressings, for example taping and bandages; impregnated suturing material; impregnated mesh, sheets, membranes, prosthetics; gels containing the compound; and so forth.

The compound may be administered to patients in a single dose in an amount which is less than, the same or greater than the amount recommended for use as an anti-rejection agent in organ transplants. For example, it is envisaged that when the compound is administered by way of local delivery, the administered amount may be from about 1 thousandth to one hundredth of the recommended systemic dose for organ transplants. Thus, where the recommended systemic dosage for organ transplants is from 1 to 2 mg per day, the amount administered locally according to the invention may be from about 1 to 2 μg/ml.

Typical applications where it would be useful to prevent scarring by inhibiting the mTOR according to the invention are: cosmetic surgery; scar revision surgery, including excision of scars and contracture release; tendon repair; nerve repair; and fibrotic or inflammatory conditions, such as de Quervain's disease, Peyronie's disease, plantar fasciitis, Dupuytren's disease, finger triggering, forms of synovitis, such as rheumatoid arthritis, after laparotomy to prevent adhesions, after brain surgery to prevent gliosis, and microsurgery, such as microvascular surgery and fallopian tube surgery. In particular, the formation of post-traumatic scarring is sought to be inhibited, and particularly scarring of mesodermal tissue, such as the skin and parencyhmal tissue surrounding tendons and nerves. As a practical example, the external covering of a breast implant may be impregnated with the compound so as to inhibit the formation of scar tissue (and subsequent capsular contraction) around the implant-.

No data has previously been published regarding the effects of mTOR inhibition only on wound healing, in particular with reference to skin, tendons or nerves.

Early gestation fetal wound healing is a model in which wound healing takes place by regeneration, rather than repair. This model is devoid of abnormal fibrosis under normal conditions. However, this type of wound healing has until now not been successfully mimicked in a post-natal wound environment. Some of the differences between fetal wound healing (where fibrosis is not observed under normal conditions) and adult wound healing are: transforming growth factor beta_! (TGF-B₁) is absent in fetal wounds, but increased levels are found in excessively fibrotic wounds; basic fibroblast growth factor (bFGF) is absent in fetal wounds; platelet derived growth factor (PDGF) is absent in fetal wounds; and interluken (IL)-4 is increased in the keloid environment. A similar phenomenon is observed in the healing of tendons. In the healing of fetal tendons, regeneration is noted with restitution of a normal tendon sheath. Here TGF-B₁ expression is also low, but is upregulated in an adult wound.

Type I collagen is the primary component of fibrotic lesions. mTOR plays an essential role in type I collagen production, via a phosphatidylinositol (Pl) 3-kinase-independent pathway. Blocking the mTOR receptor will lead to one or more of the following events: control of the T- cell proliferation cascade; control of the acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of the subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring - in any tissues; and quicker healing.

Sirolimus (also known as rapamycin) is an anti-rejection pharmaceutical compound which Is always used in conjunction with other pharmaceutical compounds to treat organ transplant patients. Sirolimus is part of a group of prodrugs that are active after forming complexes with intracytoplasmic proteins called immunophilins: binds the so-called Tacrolimus binding protein

(FK-BP). The prodrugs exert their effects on the target cell via these complexes. The immunosuppressant effects of these prodrugs appear to derive predominantly from inhibition of T-cell function and it is in these cells that their mechanisms of action have been most extensively studied.

The sirolimus: FK-BP complex directly binds to and inhibits the mammalian Target of Rapamycin (mTOR). mTOR is an intracellular pivotal regulator of cell growth and proliferation. By interfering with the function of mTOR, sirolimus inhibits the mTOR-mediated signal- transduction pathways, resulting in arrest of cell cycle G1 phase in various cell types. The increase in growth factor-mediated activation of mTOR is therefore blocked by sirolimus.

Sirolimus was selected as a suitable candidate as an inhibitor of the mTOR receptor because the immunosuppressant effects of sirolimus are derived from inhibition of T-cell function, and it is in these cells that its mechanism of action has been most extensively studied. In addition, sirolimus is the most selective kinase inhibitor known; sirolimus induces decreased TGF-β-i; sirolimus blocks bFGF induced cell proliferation; sirolimus blocks PDGF induced cell proliferation; and sirolimus inhibits IL-2 and IL-4 induced cell proliferation.

Although sirolimus has previously been administered to patients with wounds so as to prevent rejection of transplanted organs, to the applicant's knowledge it has never before been administered on its own or for the purpose of improving wound healing, and in particular in the prevention of abnormal scarring. In fact, the literature teaches away from this, and reports that implicate sirolimus in impaired wound healing, scarring and chronic cutaneous conditions abound. A person skilled in the art would therefore not expect that sirolimus would be suitable for improving wound healing.

For example, Groetzner, et a/.¹ reported bronchial airway anastomosis dehiscence in patients that received multi-drug regimens consisting of sirolimus, tacrolimus and corticosteroids and ascribed it to sirolimus administration. Valente, et at.² also reported wound healing problems with the use of sirolimus in kidney-transplant patients who were treated with multi-drug regimens. Guilbeau³ also blamed sirolimus for delayed wound healing in liver transplant patients who were treated with sirolimus and corticosteroids.

The wound healing problems described above are all associated with simultaneous use of sirolimus and other immunosuppressants, which is hardly surprising as the only indication for which sirolimus is registered, is "in combination therapy with cyclosporin and corticosteroids for the prophylaxis of organ rejection in patients receiving renal transplant"³⁴. In the light of the findings of the present invention, it is thus likely that the detrimental effects on wound healing that were observed in the prior art were due to one or more of the other immunosuppressants rather than sirolimus.

The idea to switch off the T-cell response to trauma, i.e. eliminating the immunological cascade, is based on the coincidental temporal relation between the transition from fetal to adult-like wound healing, and the transition from immunological tolerance to immunological rejection, seen in rat and sheep transplant models. Inhibiting the mTOR receptor with sirolimus effects the switching off of this T-cell response. If the fibrosis could also be switched off, so as to allow, for instance, a tendon to heal properly, stiffness would not follow.

Activated immune cells may damage peripheral nerves during inflammation. One can argue that this, together with unwanted fibrosis, may substantially interfere with surgical nerve repair. Indeed, in the absence of primary repair, a fibrotic reaction takes place around the interfascicular epineurium that effectively anchors the nerve ends in a retracted position.

In order to test the hypothesis that an mTOR inhibitor could reduce or inhibit the formation of scar tissue during wound healing, the following laboratory experiments were carried out on rats. Such example, however, is not to be construed as limiting in any way either the spirit or scope of the invention. Example

Six white adult Wistar male rats were obtained from the Medical Research Council in Edenvale, Johannesburg. The rats were provided with standard rat feed pellets and water, ad libitum. They were held in standard size cages, in pairs. The cage floors were covered with wood shavings and the room temperature was kept constant. The cages were cleaned daily.

The six rats were randomly divided into two groups, namely a control group of three rats and a test group of three rats.

Preparation of sirolimus for oral administration was performed as follows: Nine Rapamune™ 1 mg tablets from Wyeth were split into two equal halves by the use of a sterile no. 24 surgical blade. The tablet halves were stored in a marked sterile plastic bottle, in the fridge, until needed.

Immediately before administration, one tablet half was crushed until very fine. The resulting powder was then transferred into the top end of a 2 cc syringe. After the plunger was replaced, 0.5 ml of water was drawn up into the syringe and thoroughly mixed with the powder. Excess air was then expelled.

Sirolimus was administered to the test group of rats on days one, three and six, per os, per oral tube, attached to a 2 cc syringe, 0.5 mg. None of the control group received any sirolimus.

The sirolimus was administered after sedation of the rats, so as to facilitate feeding without compromising swallow reflexes (see anesthetic regimen for details).

The dosage of sirolimus for the rats was in agreement with other rat studies mentioned in literature as being safe, which is more than hundredfold the maintenance dose recommended in adults. This, together with the fact that sirolimus has a half-life of 79+12 h, was the reason for the sirolimus administration as outlined above, and not daily.

On day two of the trial, all six of the animals were anesthetized and the following surgical procedure was performed on each rat: the abdomen was cleared from hair with a commercial hair removing cream. NoHair™ cream was applied over the intended area to be used for the incision. The cream was rinsed off with tap water, after a timed application period of exactly 3 minutes. Care was thus taken to allow the minimum time of contact with the skin, to prevent the development of skin irritation. A full thickness skin incision of 3 cm in length was made with a no. 15 surgical blade. This laceration was then closed with Ethilon™ 5/0 nylon interrupted sutures.

On day four of the trial, all six of the animals were anesthetized again and the following biopsies were taken on each: A +20 x 8 mm fusiform biopsy of full thickness skin was taken from the rat's abdomen. The long axis of the specimen was aligned perpendicular to the original incision line and this sutured incision line was included in the biopsy. The biopsy specimen was delicately handled, and the nylon sutures were removed with a small sharp pair of scissors. The specimen was placed on top of a small piece of cardboard. This was done to keep the specimen from curling up and to facilitate histological sectioning (in terms of spatial orientation when viewed under the microscope). The biopsies were placed in buffered formalin, in individually marked bottles.

On day seven of the trial, the anesthetic and surgical procedures were repeated on areas of the original incision line not yet biopsied. All sutures were removed.

The original sutured incisional wounds were therefore biopsied two and five days post-incision and suturing.

The anesthetic regimen used was as follows:

Pentoparbital 5 mg / 100 ml was used for sedation and anesthesia.

The rats were weighed prior to anesthesia and recorded.

A single dose of 0.5 cc per 100 g body mass (of the abovementioned pentobarbital solution) was administered for full anesthesia, which lasted for the whole duration of the procedure. The anesthetic was administered per intraperitoneal injection. An assistant constantly monitored the anesthetized rat for breathing and for the level of anesthesia.

The first dose of sirolimus was given orally, after administration of only half of the full anesthetic dose (since no surgical anesthesia was needed at this time). This measure was taken to ensure the presence of adequate swallow reflexes. The subsequent sirolimus administrations were made in the early stages of anesthesia, while the swallow reflexes were still present.

Histology preparations were performed on the specimens as follows: Each specimen was removed from the cardboard backing and prepared for histological sections. Multiple sections were made of every specimen. Care was taken to section the specimens perpendicular to the original test incision. Haematoxylin and eosin (H&E), as well as silver nitrate stainings, were performed on alternate sections of each specimen. A histopathologist, under lightmicroscopy, then examined the specimens (Figures 1 to 17).

Results

Day two (48h) post-incision results:

Of interest was the fact that the 48h control specimens all dehisced at the time of taking of biopsies and removal of sutures. All test specimens dehisced at the time of histological specimen preparation.

Control group: Normal acute inflammation with neutrophil infiltration, early granulation tissue formation and proteolytic activity on the wound edge.

Test group: No significant neutrophil infiltration, granulation tissue formation or proteolytic activity on the wound edge.

Day five post-incision results:

None of the test or control group animals had wound dehiscence after suture removal.

Control group: Granulation tissue formation, numerous fibroblasts with irregular collagen deposition - early scar formation and thickened epidermis.

Test group: Normal dermal collagen architecture, very few fibroblasts, no clearly identifiable scar formation, thickened epidermis. It was very difficult to determine if the sections examined were representative of the surgical incision, due to the absence of scar tissue. The only signs were a step or wedge contour deformity of the epidermis, as well as the expected thickened epidermis over the wound area.

These results are discussed below in more detail with reference to the figures.

Figure 1 shows the wound edge, of one half of a control specimen at 48h. An acute inflammatory reaction is shown in figure 2, with numerous neutrophils indicated with arrows. The expected area of proteolytic activity, a consequence of the reaction seen above, is shown between the broad arrows in figure 3. Note the abrupt transition between normal, uninjured dermal collagen, and the zone of injury with scab formation and debris (thin arrow). Figures 5 and 6a show the test group wound edge, clearly without this acute inflammatory reaction, and without the clear zone of proteolytic activity and debris.

Figures 6b and 9 show the early day 5 scar, between the arrows, in the control group. Fibroblast proliferation is visible in this scar. The abnormal collagen architecture is also clearly visible in figures 7, 8 and 10. Thickening of the epidermis, as seen in figures 7 and 10, is expected in an early wound. Reepithelialization has therefore taken place.

The day 5 test group did not exhibit the fibroblast proliferation seen on the control slides. Rather, a difficulty identifying the wound area was encountered. Figure 11 shows the likely site of injury, with a notch in the epidermis, as well as thickened epidermis, as expected with reepithelialization of a wound.

The absence of scar in the day 5 test group wound, shown in figure 12, is indicated by the broad arrows. The silver staining method clearly shows normal collagen fibre architecture. Figure 13 is a higher magnification than shown in figure 12. No interruption seen in the collagen fibre orientation or pattern.

Figures 14 and show day 5 test group slides. A scab can be seen in figure 14, indicating the area of trauma. Deep to this scab, lies an area of contour irregularity of the epidermis. This is therefore most probably the area of wounding. No scar can be seen deep to the mentioned area.

Figure 15 shows the silver staining. Here the normal dermal collagen architecture is clearly visible.

The above results can therefore be summarized as: Control group: Normal scar formation

Test group: Cannot see surgical incision

In order to facilitate identification of the incision line histologically, the test was repeated, but with India ink painted onto the two wound edges, before suturing. This would, however, give rise to a possible foreign body reaction, which could interfere with the test. The result did indeed indicate the rats to form a fibrotic reaction toward the India ink, and also showed good foreign body lymphatic clearance, in spite of Sirolimus administration.

A fibrotic reaction is clearly visible in figure 16, representing the day 5 India ink test group. Early scar formation was therefore initiated. The charcoal particles are being cleared away into the depth, by lymphatic action.

Figure 17 shows the abnormal dermal collagen pattern in this group.

Discussion

Administration of sirolimus, prior to incisional wounding and during the acute healing phase, during which time histological specimens were taken, was shown to alter the wound healing process histologically. Histology of the wounds showed normal scar formation in the control group, but poorly recognizable wounds on the test animals, without wound dehiscence. The sirolimus-associated wounds shared a number of characteristics with non-scarring fetal wounds, viz. the absence of scar-like dermal collagen architecture, an increase in epidermal thickening overlying the incision, the absence of normal post-injury inflammation, the absence of normal post-injury neovascularization and the presence of foreign body induced fibrosis.

The histopathologist was unable to find the incision on the histological specimen, on both H&E and silver staining slides. The only signs of where the incision was placed, were:

1. An epidermal contour irregularity. It stands to reason, that an incised and sutured wound, five days old, might very likely produce this result. An overlying scab would enhance the suspicion.

2. A thickened epidermal section, overlying the healing wound. This observation fits in with normal, as well as scarless fetal wound healing.

Histologically the dermal connective pattern was normal. No significant inflammation or neovascularization was noted.

In addition, the results showed no evidence that sirolimus stops or interferes with wound healing, since there was no break down of any test wound. An interesting observation was made in this regard. The control group had wound dehiscence at the time of the 48h biopsy procedure (i.e. the biopsy specimen spontaneously separated into two pieces, without force applied beyond that of the biopsy blade). The 48h test group specimens, however, only dehisced during the histology preparation process. This is probably attributable to the fact that no proteolysis took place in the wound site in the test group, therefore allowing the healing process to continue more rapidly, and hence more tensile strength. Conclusion

This process is induced by switching off the immunological response to a wound (in this case, a surgical incision), which is afforded by the administration of sirolimus. This process is at least possible in the acute wound healing phase, whilst the rat is receiving the drug.

References

1. Groetzner JKF, et al: Airway Anastomosis Complications in de novo Lung Transplantation with Sirolimus- Based Immunosuppression J Heart Lung Transplant 23:632-638, 2004

2. Valente JF, et al: Comparison of Sirolimus vs. Mycophenolate Mofetil on Surgical Complications and Wound Healing in Adult Kidney Transplantation Am J Transplant 3:1128-1134, 2003

3. Guilbeau JM: Delayed Wound Healing with Sirolimus after Liver Transplant Ann Pharmacother 36:1391- 1395, 2002 4. Package Insert: Rapamune® 1mg Tablets Wyeth South Africa (Pty) Ltd, 2000

Claims

CLAIMS:

1. A method of inhibiting the formation of scar tissue during wound healing, the method including the step of administering to a patient in need thereof a compound which inhibits the mammalian Target of Rapamycin (mTOR).

2. A method according to claim 1 , wherein the compound is sirolimus or a derivative or pharmaceutically acceptable salt thereof.

3. A method according to either of claims 1 or 2, wherein the compound is everolimus.

4. A method according to any one of claims 1 to 3, wherein the wound is from an insult to the patient.

5. A method according to claim 4, wherein the insult is from surgery.

6. A method according to claim 4, wherein the insult is an injury.

7. A method according to any one of claims 1 to 3, wherein the wound is a result of a disease process.

8. A method according to any one of claims 1 to 7, wherein the compound is administered alone.

9. A method according to any one of claims 1 to 7, wherein the compound is administered in combination with one or more other pharmaceutical compounds.

10. A method according to any one of claims 1 to 9, wherein the compound is administered to the patient prior to infliction of the wound.

11. A method according to any one of claims 1 to 9, wherein the compound is administered to the patient during infliction of the wound.

12. A method according to any one of claims 1 to 9, wherein the compound is administered to the patient after infliction of the wound.

13. A method according to any one of claims 1 to 12, wherein the method of treatment results in one or more of the following responses: control of the T-cell proliferation cascade; control of acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring; and quicker healing.

14. A method of inhibiting the development of insult-related fibrosis in a patient, the method including the step of administering to the patient a compound which inhibits the mammalian Target of Rapamycin (mTOR).

15. A method according to claim 14, wherein the compound is sirolimus or a derivative or pharmaceutically acceptable salt thereof.

16. A method according to either of claims 14 or 15, wherein the compound is everolimus.

17. A method according to any one of claims 14 to 16, wherein the wound is from an insult to the patient.

18. A method according to claim 17, wherein the insult is from surgery.

19. A method according to claim 17, wherein the insult is an injury.

20. A method according to any one of claims 14 to 16, wherein the wound is a result of a disease process.

21. A method according to any one of claims 14 to 20, wherein the compound is administered alone.

22. A method according to any one of claims 14 to 20, wherein the compound is administered in combination with one or more other pharmaceutical compounds.

23. A method according to any one of claims 14 to 22, wherein the compound is administered to the patient prior to infliction of the wound.

24. A method according to any one of claims 14 to 22, wherein the compound is administered to the patient during infliction of the wound.

25. A method according to any one of claims 14 to 22, wherein the compound is administered to the patient after infliction of the wound.

26. A method according to any one of claims 14 to 25, wherein the method of treatment results in one or more of the following responses: control of the T-cell proliferation cascade; control of acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring; and quicker healing.

27. A method of suppressing inflammation in response to an insult, the method including the step of administering to a patient in need thereof a compound which inhibits the mammalian Target of Rapamycin (mTOR).

28. A method according to claim 27, wherein the compound is sirolimus or a derivative or pharmaceutically acceptable salt thereof.

29. A method according to either of claims 27 or 28, wherein the compound is everolimus.

30. A method according to any one of claims 27 to 29, wherein the wound is from an insult to the patient.

31. A method according to claim 30, wherein the insult is from surgery.

32. A method according to claim 30, wherein the insult is an injury.

33. A method according to any one of claims 27 to 29, wherein the wound is a result of a disease process.

34. A method according to any one of claims 27 to 33, wherein the compound is administered alone.

35. A method according to any one of claims 27 to 33, wherein the compound is administered in combination with one or more other pharmaceutical compounds.

36. A method according to any one of claims 27 to 35, wherein the compound is administered to the patient prior to infliction of the wound.

37. A method according to any one of claims 27 to 35, wherein the compound is administered to the patient during infliction of the wound.

38. A method according to any one of claims 27 to 35, wherein the compound is administered to the patient after infliction of the wound.

39. A method according to any one of claims 27 to 38, wherein the method of treatment results in one or more of the following responses: control of the T-cell proliferation cascade; control of acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring; and quicker healing.

40. The use of a compound which inhibits the mammalian Target of Rapamycin (mTOR) in a method of manufacturing a medicament for use in a method of inhibiting the development of insult-related fibrosis, suppressing inflammation in response to an insult and/or inhibiting the formation of scar tissue during wound healing.

41. The use according to claim 40, wherein the compound is sirolimus or a derivative or pharmaceutically acceptable salt thereof.

42. The use according to either of claims 40 or 41 , wherein the compound is everolimus.

43. The use according to any one of claims 40 to 42, wherein the wound is from an insult to the patient.

44. The use according to claim 43, wherein the insult is from surgery.

45. The use according to claim 43, wherein the insult is an injury.

46. The use according to any one of claims 40 to 42, wherein the wound is a result of a disease process.

47. The use according to any one of claims 40 to 46, wherein the compound is administered alone.

48. The use according to any one of claims 40 to 46, wherein the compound is administered in combination with one or more other pharmaceutical compounds.

49. The use according to any one of claims 40 to 48, wherein the compound is administered to the patient prior to infliction of the wound.

50. The use according to any one of claims 40 to 48, wherein the compound is administered to the patient during infliction of the wound.

51. The use according to any one of claims 40 to 48, wherein the compound is administered to the patient after infliction of the wound.

52. The use according to any one of claims 40 to 51, wherein the method of treatment results in one or more of the following responses: control of the T-cell proliferation cascade; control of acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring; and quicker healing.

53. A compound which inhibits the mammalian Target of Rapamycin (mTOR) for use in a method of inhibiting the development of insult-related fibrosis, suppressing inflammation in response to an insult and/or inhibiting the formation of scar tissue during wound healing.

54. A compound according to claim 53, which is sirolimus or a derivative or pharmaceutically acceptable salt thereof.

55. A compound according to either of claims 53 or 54, which is everolimus.

56. A compound according to any one of claims 53 to 55, wherein the wound is from an insult to the patient.

57. A compound according to claim 56, wherein the insult is from surgery.

58. A compound according to claim 56, wherein the insult is an injury.

59. A compound according to any one of claims 53 to 55, wherein the wound is a result of a disease process.

60. A compound according to any one of claims 53 to 59, wherein the compound is administered alone.

61. A compound according to any one of claims 53 to 59, wherein the compound is administered in combination with one or more other pharmaceutical compounds.

62. A compound according to any one of claims 53 to 61 , wherein the compound is administered to the patient prior to infliction of the wound.

63. A compound according to any one of claims 53 to 61 , wherein the compound is administered to the patient during infliction of the wound.

64. A compound according to any one of claims 53 to 61 , wherein the compound is administered to the patient after infliction of the wound.

65. A compound according to any one of claims 53 to 64, wherein the method of treatment results in one or more of the following responses: control of the T-cell proliferation cascade; control of acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring; and quicker healing.

66. An article of manufacture for inhibiting the development of insult-related fibrosis, suppressing inflammation in response to an insult and/or inhibiting the formation of scar tissue during wound healing, the article including a compound which inhibits the mammalian Target of Rapamycin (mTOR).

67. An article according to claim 66, wherein the compound is sirolimus or a derivative or pharmaceutically acceptable salt thereof.

68. An article according to either of claims 66 or 67, wherein the compound is everolimus.

69. An article according to any one of claims 66 to 68, which is selected from the group consisting of a surgical implant, a medical garment, a medical dressing, medical staples, suture material, mesh, sheets, membranes and prosthetics.

70. An article according to claim 69, wherein the medical dressing is a bandage,

71. An article according to claim 69, wherein the medical dressing is a plaster.

72. An article according to any one of claims 66 to 71 , which includes a delayed release formulation of the compound.

73. An article according to any one of claims 66 to 72, wherein the wound is from an insult to the patient.

74. An article according to claim 73, wherein the insult is from surgery.

75. An article according to claim 73, wherein the insult is an injury.

76. An article according to any one of claims 66 to 72, wherein the wound is a result of a disease process.

77. An article according to any one of claims 66 to 76, wherein the compound is administered alone.

78. An article according to any one of claims 66 to 76, wherein the compound is administered in combination with one or more other pharmaceutical compounds.

79. An article according to any one of claims 66 to 78, wherein the compound is administered to the patient prior to infliction of the wound.

80. An article according to any one of claims 66 to 78, wherein the compound is administered to the patient during infliction of the wound.

81. An article according to any one of claims 66 to 78, wherein the compound is administered to the patient after infliction of the wound.

82. An article according to any one of claims 66 to 81 , wherein the method of treatment results in one or more of the following responses: control of the T-cell proliferation cascade; control of acute inflammatory cell migration and activation; control of wound environment proteolytic and inflammatory tissue damage; control of subsequent fibroblast proliferation and collagen production; control of abnormal collagen architecture; control of the fibrotic reaction; decrease in scarring; and quicker healing.

83. A method of inhibiting the formation of scar tissue during wound healing according to claim 1 , substantially as herein described with reference to any one of the illustrative examples.

84. A method of inhibiting the development of insult-related fibrosis in a patient according to claim 14, substantially as herein described with reference to any one of the illustrative examples.

85. A method of suppressing inflammation in response to an insult according to claim 27, substantially as herein described with reference to any one of the illustrative examples.

86. A compound according to claim 53, substantially as herein described with reference to any one of the illustrative examples.

87. An article of manufacture according to claim 66, substantially as herein described with reference to any one of the illustrative examples.