Topical and local controlled release of stratifin for the improvement of hypertrophic scarring in open and surgically closed wounds

Hypertrophic scar (HS), which results from the uncontrolled synthesis and excessive deposition of extracellular matrix (ECM) at sites of dermal injury, represents an undesirable endpoint of wound healing. Stratifin (SFN) was recently identified as a potent matrix methaloproteinase-1 (MMP-1) stimulatory factor in dermal fibroblasts. In this research project, it is hypothesized that stratifin can modulate the deposition of ECM components and prevent HS formation when it is applied topically to open wounds or locally delivered to surgically closed wounds. Four specific objectives were accomplished in this project. Under objective 1, a hydrogel /microsphere dermal implant was fabricated, specifically to be placed in surgical wounds before closure and locally deliver stratifin in a controlled manner to reduce HS formation. Microencapsulating stratifin complexed chitosan particles into PLGA microspheres allowed bioactive stratifin to be controllably released over 30 days with a reduced burst release. Under objective 2, use of a rat surgical wound model showed that the local controlled delivery of stratifin markedly reduced fibrosis and inflammation induced by drug-free implants, confirmed by a reduced collagen deposition, total tissue cellularity, and infiltrated CDHypertrophic scar (HS), which results from the uncontrolled synthesis and excessive deposition of extracellular matrix (ECM) at sites of dermal injury, represents an undesirable endpoint of wound healing. Stratifin (SFN) was recently identified as a potent matrix methaloproteinase-1 (MMP-1) stimulatory factor in dermal fibroblasts. In this research project, it is hypothesized that stratifin can modulate the deposition of ECM components and prevent HS formation when it is applied topically to open wounds or locally delivered to surgically closed wounds. Four specific objectives were accomplished in this project. Under objective 1, a hydrogel /microsphere dermal implant was fabricated, specifically to be placed in surgical wounds before closure and locally deliver stratifin in a controlled manner to reduce HS formation. Microencapsulating stratifin complexed chitosan particles into PLGA microspheres allowed bioactive stratifin to be controllably released over 30 days with a reduced burst release. Under objective 2, use of a rat surgical wound model showed that the local controlled delivery of stratifin markedly reduced fibrosis and inflammation induced by drug-free implants, confirmed by a reduced collagen deposition, total tissue cellularity, and infiltrated CD³⁺ immune cells. Under objective 3, the anti-fibrogenic effect of topically applied stratifin was investigated on open wounds created in a rabbit ear fibrotic model. Qualitative wound assessment showed a reduced HS in wounds treated with stratifin-impregnated CMC gel (0.002%, w/w) applied twice a day, confirmed with reduced scar volume including deposited collagen and total tissue cellularity. Under objective 4, CMC gel was modified into a thermoreversible emulgel, which demonstrated a significant effect on scar reduction through its occlusive effect. Using this emulgel and combining stratifin with acetylsalicylic acid significantly reduced HS, even with once a day application. In conclusion, the findings presented in this thesis provide further support for the importance and feasibility of using stratifin as an MMP-1 stimulatory factor for the improvement/prevention of dermal fibrosis in open and surgically closed wounds. These findings also provide additional information regarding controlled delivery of proteins to any kind of wounds, such as those resulting from surgical or burns. immune cells. Under objective 3, the anti-fibrogenic effect of topically applied stratifin was investigated on open wounds created in a rabbit ear fibrotic model. Qualitative wound assessment showed a reduced HS in wounds treated with stratifin-impregnated CMC gel (0.002%, w/w) applied twice a day, confirmed with reduced scar volume including deposited collagen and total tissue cellularity. Under objective 4, CMC gel was modified into a thermoreversible emulgel, which demonstrated a significant effect on scar reduction through its occlusive effect. Using this emulgel and combining stratifin with acetylsalicylic acid significantly reduced HS, even with once a day application. In conclusion, the findings presented in this thesis provide further support for the importance and feasibility of using stratifin as an MMP-1 stimulatory factor for the improvement/prevention of dermal fibrosis in open and surgically closed wounds. These findings also provide additional information regarding controlled delivery of proteins to any kind of wounds, such as those resulting from surgical or burns.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat