Platelet lysate mucohadesive formulation to treat oral mucositis in graft versus host disease patients: a new therapeutic approach

Abstract

Optimal treatment of oral mucositis (OM) due to graft versus host disease (GvHD) is currently not available. Platelet-derived growth factors (PDGFs) have high capability for tissue healing and may play a role in repairing the mucosal barrier. The aim of the present work was to develop a mucoadhesive formulation to administer platelet lysate to oral cavity prolonging contact time of platelet lysate with oral mucosa. The mucoadhesive formulation was characterized for in vitro properties (PDGF-AB concentration, mucoadhesive properties, cytotoxicity, fibroblast proliferation, wound healing). Moreover, a preliminary clinical study on seven GvHD patients with OM refractory to other therapies was conducted, to evaluate feasibility, safety, and efficacy. GVPL (mucoadhesive gel vehicle mixed with platelet lysate)showed good mucoadhesive properties; additionally, it was characterized by good biocompatibility in vitro on fibroblasts and it was able to enhance fibroblast proliferation and wound healing, maintaining the efficacy for up to 14 days following storage at 2-8°C. In vivo, clinical response was good-to-complete in five, fair in one, none in the remaining one. The in vitro results indicate that GVPL has optimal mucoadhesive and healing enhancer properties, maintained over time (up to 14 days); preliminary clinical results suggest that oral application of platelet lysate-loaded mucoadhesive formulation is feasible, safe, well tolerated, and effective. A larger controlled randomized study is needed.

Fig. 1

Mucoadhesive properties of the vehicle (GV) and of the formulation (GVPL): maximum force of mucoadhesion (millinewton) (median and IQR; n = 6). Comparisons: among GV, blank vs mucin p < 0.001; among GVPL, blank vs mucin p < 0.001; mucin GV vs mucin GVPL, p = 0.37

Fig. 2

Percent viability of fibroblasts in contact with Carbopol 974P samples having different concentrations (median and IQR; n = 8)

Fig. 3

Percentage of fibroblast proliferation in presence of two dilutions (1:20 or 1:40) of PL or of PL in GVPL after different times storage (T0 time zero, 48 h 2 days, 7 d 7 days, 10 d 10 days, 14 d 14 days) (median and IQR; n = 32 at each time point). t = 0: control vs PL 1:20, p < 0.001; control vs PL 1/40, <0.001; control vs GVPL 1/20, p = 0.202; control vs GVPL 1/40, p < 0.001; PL 1/20 vs PL 1/40, p = 0.392; GVPL 1/20 vs GVPL 1/40, p = 0.012; PL 1/20 vs GVPL 1/20, p ≤ 0.001; PL 1/40 vs GVPL 1/40, p ≤ 0.001. t = 48 h: control vs PL 1/20, p < 0.001; control vs PL 1/40, p < 0.001; control vs GVPL 1/20, p = 0.113; control vs GVPL 1/40, p < 0.001; PL 1/20 vs PL 1/40, p = 0.491; GVPL 1/20 vs GVPL 1/40, p = 0.002; PL 1/20 vs GVPL 1/20, p ≤ 0.001; PL 1/40 vs GVPL 1/40, p = 0.101. t = 7 d: control vs PL 1/20, p < 0.001; control vs PL 1/40, p = 0.051; control vs GVPL 1/20, p = 0.312; control vs GVPL 1/40, p = 0.008; PL 1/20 vs PL 1/40, p = 0.130; GVPL 1/20 vs GVPL 1/40, p = 0.065; PL 1/20 vs GVPL 1/20, p = 0.021; PL 1/40 vs GVPL 1/40, p = 0.258. t = 14 d: control vs PL 1/20, p < 0.001; control vs PL 1/40, p < 0.001; control vs GVPL 1/20, p = 0.197; control vs GVPL 1/40, p = 0.001; PL 1/20 vs PL 1/40, p = 0.075; GVPL 1/20 vs GVPL 1/40, p = 0.014; PL 1/20 vs GVPL 1/20, p ≤ 0.001; PL 1/40 vs GVPL 1/40, p = 0.048

Fig. 4

Microphotographs of fibroblasts at time 0 (t = 0) and after exposure to a PL 1/20 and b PL 1/20 in GVPL at 72 and 96 h