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Tissue-Engineered Skin Substitute Enhances Wound Healing after Radiation Therapy

Busra MF, Chowdhury SR, bin Ismail F, bin Saim A, Idrus RB

Adv Skin Wound Care, 2016 Mar;29(3):120-9.
PMID: 26866868 DOI: 10.1097/01.ASW.0000480556.78111.e4

OBJECTIVE: When given in conjunction with surgery for treating cancer, radiation therapy may result in impaired wound healing, which, in turn, could cause skin ulcers. In this study, bilayer and monolayer autologous skin substitutes were used to treat an irradiated wound.
MATERIALS AND METHODS: A single dose of 30 Gy of linear electron beam radiation was applied to the hind limb of nude mice before creating the skin lesion (area of 78.6 mm). Monolayer tissue-engineered skin substitutes (MTESSs) were prepared by entrapping cultured keratinocytes in fibrin matrix, and bilayer tissue-engineered skin substitutes (BTESSs) were prepared by entrapping keratinocytes and fibroblasts in separate layers. Bilayer tissue-engineered skin substitute and MTESS were implanted to the wound area. Gross appearance and wound area were analyzed to evaluate wound healing efficiency. Skin regeneration and morphological appearance were observed via histological and electron microscopy. Protein expressions of transforming growth factor β1 (TGF-β1), platelet-derived growth factor BB (PDGF-BB), and vascular endothelial growth factor (VEGF) in skin regeneration were evaluated by immunohistochemistry (IHC).
RESULTS: Macroscopic observation revealed that at day 13, treatments with BTESS completely healed the irradiated wound, whereas wound sizes of 1.1 ± 0.05 and 6.8 ± 0.14 mm were measured in the MTESS-treated and untreated control groups, respectively. Hematoxylin-eosin (H&E) analysis showed formation of compact and organized epidermal and dermal layers in the BTESS-treated group, as compared with MTESS-treated and untreated control groups. Ultrastructural analysis indicates maturation of skin in BTESS-treated wound evidenced by formation of intermediate filament bundles in the dermal layer and low intercellular space in the epidermal layer. Expressions of TGF-β1, PDGF-BB, and VEGF were also higher in BTESS-treated wounds, compared with MTESS-treated wounds.
CONCLUSIONS: These results indicate that BTESS is the preferred treatment for irradiated wound ulcers.
Safety and efficacy of dermal fibroblast conditioned medium (DFCM) fortified collagen hydrogel as acellular 3D skin patch

Maarof M, Mh Busra MF, Lokanathan Y, Bt Hj Idrus R, Rajab NF, Chowdhury SR

Drug Deliv Transl Res, 2019 02;9(1):144-161.
PMID: 30547385 DOI: 10.1007/s13346-018-00612-z

Skin substitutes are one of the main treatments for skin loss, and a skin substitute that is readily available would be the best treatment option. However, most cell-based skin substitutes require long production times, and therefore, patients endure long waiting times. The proteins secreted from the cells and tissues play vital roles in promoting wound healing. Thus, we aimed to develop an acellular three-dimensional (3D) skin patch with dermal fibroblast conditioned medium (DFCM) and collagen hydrogel for immediate treatment of skin loss. Fibroblasts from human skin samples were cultured using serum-free keratinocyte-specific media (KM1 or KM2) and serum-free fibroblast-specific medium (FM) to obtain DFCM-KM1, DFCM-KM2, and DFCM-FM, respectively. The acellular 3D skin patch was soft, semi-solid, and translucent. Collagen mixed with DFCM-KM1 and DFCM-KM2 showed higher protein release compared to collagen plus DFCM-FM. In vitro and in vivo testing revealed that DFCM and collagen hydrogel did not induce an immune response. The implantation of the 3D skin patch with or without DFCM on the dorsum of BALB/c mice demonstrated a significantly faster healing rate compared to the no-treatment group 7 days after implantation, and all groups had complete re-epithelialization at day 17. Histological analysis confirmed the structure and integrity of the regenerated skin, with positive expression of cytokeratin 14 and type I collagen in the epidermal and dermal layer, respectively. These findings highlight the possibility of using fibroblast secretory factors together with collagen hydrogel in an acellular 3D skin patch that can be used allogeneically for immediate treatment of full-thickness skin loss.
Fulltext Dual-action of thermoresponsive gels containing DsiRNA-loaded gold nanoparticles for diabetic wound therapy: Characterization, in vitro safety and healing efficacy

Nor Azlan AYH, Katas H, Habideen NH, Mh Busra MF

Saudi Pharm J, 2020 Nov;28(11):1420-1430.
PMID: 33250649 DOI: 10.1016/j.jsps.2020.09.007

Diabetic wounds are difficult to treat due to multiple causes, including reduced blood flow and bacterial infections. Reduced blood flow is associated with overexpression of prostaglandin transporter (PGT) gene, induced by hyperglycaemia which causing poor vascularization and healing of the wound. Recently, gold nanoparticles (AuNPs) have been biosynthesized using cold and hot sclerotium of Lignosus rhinocerotis extracts (CLRE and HLRE, respectively) and capped with chitosan (CS) to produce biocompatible antibacterial nanocomposites. The AuNPs have shown to produce biostatic effects against selected gram positive and negative bacteria. Therefore, in this study, a dual therapy for diabetic wound consisting Dicer subtract small interfering RNA (DsiRNA) and AuNPs was developed to improve vascularization by inhibiting PGT gene expression and preventing bacterial infection, respectively. The nanocomposites were incorporated into thermoresponsive gel, made of pluronic and polyethylene glycol. The particle size of AuNPs synthesized using CLRE (AuNPs-CLRE) and HLRE (AuNPs-HLRE) was 202 ± 49 and 190 ± 31 nm, respectively with positive surface charge (+30 to + 45 mV). The thermoresponsive gels containing DsiRNA-AuNPs gelled at 32 ± 1 °C and released the active agents in sufficient amount with good texture and rheological profiles for topical application. DsiRNA-AuNPs and those incorporated into thermoresponsive pluronic gels demonstrated high cell viability, proliferation and cell migration rate via in vitro cultured cells of human dermal fibroblasts, indicating their non-cytotoxicity and wound healing properties. Taken together, the thermoresponsive gels are expected to be useful as a potential dressing that promotes healing of diabetic wounds.
Development and physicochemical analysis of genipin-crosslinked gelatine sponge as a potential resorbable nasal pack

Selvarajah J, Mh Busra MF, Bin Saim A, Bt Hj Idrus R, Lokanathan Y

J Biomater Sci Polym Ed, 2020 09;31(13):1722-1740.
PMID: 32458725 DOI: 10.1080/09205063.2020.1774841

Nasal injury following nasal surgery is an adverse consequence, and prompt treatment should be initiated. Nasal packing, either non-absorbable or absorbable, are commonly used after nasal surgery to prevent bleeding and promote wound healing. In the current study, a novel gelatine sponge crosslinked with genipin was evaluated for suitability to be used as nasal packing and compared to one of the frequently used commercial nasal packing made up of polyurethane. Gelatine at 7% and 10% (w/v) concentration were crosslinked with varying concentrations of genipin, 0.5%, 0.25%, and 0.2% (v/v). The gelatine sponges were further characterised by its water uptake ability, biodegradation, water vapour transmission rate, porosity, contact angle, chemical composition, crosslinking degree, and mechanical properties. The gelatine sponges absorbed five times more water than their dry weight and were degraded within five days. The water vapour transmission rate of the gelatine sponges was 1187.7 ± 430.2 g/(m-2 day) for 7% gelatine and 779.4 ± 375.5 g/(m-2 day) for 10% gelatine. Crosslinking of gelatine with genipin resulted in lower porosity and did not affect the wettability of gelatine sponge (contact angle: 95.3 ± 12.1° for 7% gelatine and 88.4 ± 7.2° for 10% gelatine). In terms of biodegradability, the gelatine sponges took 24-48 h to degrade completely. Genipin crosslinking improved the degradation resistance and mechanical strength of gelatine sponge. The physical and chemical properties of the gelatine sponge, i.e. biodegradability and mechanical durability, support its potential as nasal packing.
Fulltext Antibacterial activity of biosynthesized gold nanoparticles using biomolecules from Lignosus rhinocerotis and chitosan

Katas H, Lim CS, Nor Azlan AYH, Buang F, Mh Busra MF

Saudi Pharm J, 2019 Feb;27(2):283-292.
PMID: 30766441 DOI: 10.1016/j.jsps.2018.11.010

A simple, cost-effective, and environmentally friendly method is needed for synthesizing metal nanoparticles, including gold nanoparticles (AuNPs). In this study, AuNPs were synthesized with Lignosus rhinocerotis sclerotial extract (LRE) and chitosan (CS) as reducing and stabilizing agents, respectively. Different LRE concentrations from cold and hot water extraction (CWE and HWE, respectively) were used to reduce chloroauric acid (HAuCl4) to form AuNPs. Positively charged chitosan stabilized AuNPs (CS-AuNPs) mediated by LRE exhibited a surface plasmon resonance (SPR) band at 533 nm. The CS-AuNPs synthesized using CWE had a smaller particle size (49.5 ± 6.7-82.4 ± 28.0 nm) compared to that of the HWE samples (80.3 ± 23.4-125.3 ± 41.5 nm), depending on LRE concentration. FTIR results suggested protein and polysaccharides in LRE were the sources of reducing power, reducing gold ions to AuNPs. CS-AuNPs were mostly spherical with higher LRE concentrations, whereas some triangular, pentagonal, irregular, and rod shaped AuNPs were observed at lower LRE concentrations. CS-AuNPs mediated by LRE displayed effective antibacterial activity against gram-negative (Pseudomonas aeruginosa and Escherichia coli) and gram-positive bacteria (Staphylococcus aureus and Bacillus sp.). Thus, the biosynthesized AuNPs using LRE and chitosan provide opportunities for developing stable and eco-friendly nanoparticles with effective antibacterial properties.
Collagen Type I: A Versatile Biomaterial

Chowdhury SR, Mh Busra MF, Lokanathan Y, Ng MH, Law JX, Cletus UC, et al.

Adv Exp Med Biol, 2018 10 26;1077:389-414.
PMID: 30357700 DOI: 10.1007/978-981-13-0947-2_21

Collagen type I is the most abundant matrix protein in the human body and is highly demanded in tissue engineering, regenerative medicine, and pharmaceutical applications. To meet the uprising demand in biomedical applications, collagen type I has been isolated from mammalians (bovine, porcine, goat and rat) and non-mammalians (fish, amphibian, and sea plant) source using various extraction techniques. Recent advancement enables fabrication of collagen scaffolds in multiple forms such as film, sponge, and hydrogel, with or without other biomaterials. The scaffolds are extensively used to develop tissue substitutes in regenerating or repairing diseased or damaged tissues. The 3D scaffolds are also used to develop in vitro model and as a vehicle for delivering drugs or active compounds.
The effects of human serum to the morphology, proliferation and gene expression level of the respiratory epithelium in vitro

Yunus MH, Siang KC, Hashim NI, Zhi NP, Zamani NF, Sabri PP, et al.

Tissue Cell, 2014 Aug;46(4):233-40.
PMID: 24973262 DOI: 10.1016/j.tice.2014.05.003

The culture of human airway epithelial cells has played an important role in advancing our understanding of the metabolic and molecular mechanisms underlying normal function and disease pathology of airway epithelial cells. The present study focused on investigating the effects of human serum (HS) on the qualitative and quantitative properties of the human respiratory epithelium compared to the fetal bovine serum (FBS), as a supplement in culture. Respiratory epithelial (RE) cells derived from human nasal turbinate were co-cultured with fibroblasts, subsequently separated at 80-90% confluency by differential trypsinization. RE cells were then sub-cultured into 2 different plates containing 5% allogenic HS and FBS supplemented media respectively up to passage 1 (P1). Cell morphology, growth rate, cell viability and population doubling time were assessed under light microscope, and levels of gene expression were measured via real time reverse transcriptase-polymerase chain reaction (qRT-PCR). RE cells appeared as polygonal shape and expanded when cultured in HS whereas RE cells in FBS were observed to be easily matured thus limit the RE cells expansion. Proliferation rate of RE cells in HS supplemented media (7673.18 ± 1207.15) was 3 times higher compared to RE in FBS supplemented media (2357.68 ± 186.85). Furthermore, RE cells cultured in HS-supplemented media required fewer days (9.15 ± 1.10) to double in numbers compared to cells cultured in FBS-supplemented media (13.66 ± 0.81). Both the differences were significant (p<0.05). However, there were no significant differences in the viability of RE cells in both groups (p=0.105). qRT-PCR showed comparable expressions of gene Cytokeratin-14 (CK-14), Cytokeratin-18 (CK-18) and Mucin-5 subtype B (MUC5B) in RE cells cultured in both groups (p>0.05). In conclusion, HS is a comparatively better choice of media supplement in accelerating growth kinetics of RE cells in vitro thus producing a better quality of respiratory epithelium for future tracheal reconstruction.