Charged Beads Enhance Cutaneous Wound Healing in Rhesus Non-Human Primates

Abstract

Enhanced cutaneous wound healing by positively charged cross-linked diethylaminoethyl dextran beads (CLDD) was studied in a standardized incisional wound model in 20 adult and 20 geriatric Macaca mulatta (rhesus) partitioned equally over five time periods. Physiologic saline served as a control. Soft-tissue linear incisions were prepared between and 1 cm inferior to the scapulae. There were four incisions per rhesus; each incision was 1.5 cm long with 1 cm of undisturbed tissue between incisions, and both the experimental CLDD and physiologic saline treatments were administered to each rhesus. The incision treatments were either CLDD and soft-tissue closure with 4-0 BioSyn sutures or sterile physiologic saline and closure with 4-0 BioSyn sutures. The hypothesis was CLDD would enhance cutaneous wound repair. Verification of the hypothesis consisted of clinical examinations and histologic and tensiometric evaluations on biopsy specimens at 10 and 15 days, whereas 5-day and 2- and 4-month groups were assessed clinically and biopsy specimens were assessed histologically. The clinical course of healing for all groups was unremarkable. At 10 days, incisions in adult rhesus treated with CLDD had a 30-percent greater tensile strength compared with the physiologic saline-treated incisions (p = 0.01), whereas for geriatric rhesus, the CLDD treatment proved to be 15 percent greater in tensile strength compared with the physiologic saline cohort (p = 0.11). By day 15, incisions in adult rhesus were 26 percent stronger than the saline treatment group (p = 0.07), and the difference was 36 percent (p = 0.02) for the geriatric rhesus. From 5 through 15 days, histologic observations revealed a gradual decrease in quantity and integrity of CLDD, with no remnants of CLDD at either 2 or 4 months. Macrophages and multinucleated giant cells were localized in the dermis and were associated with the CLDD. These cells decreased commensurately with the decrease of CLDD beads. The data suggest that CLDD can enhance significantly the tensile properties of healing cutaneous wounds in both adult and geriatric rhesus. Moreover, if the wound healing is enhanced in geriatric patients, this finding may be clinically germane to conditions where wound healing is compromised, such as in diabetics and patients on steroids.

Stimulation of wound healing by positively charged dextran beads depends upon clustering of beads and cells in close proximity to the wound

“…Our previous studies show that DEAE A25 beads increase wound breaking strength in both rats and nonhuman primates. [3][4][5][6] Other studies have shown that the material can cause bone formation in the rabbit mandible. 18 The goal of the present study was to evaluate the interaction between cells and a variety of positively charged beads.…”

Biocompatibility of Injectable Microspheres

“…These dextran microspheres caused severe granuloma formation [32,72] until they are resorbed after 1 to 2 years (Figure 8). Burgess [73] positively charged dextran beads of 40-120µm in diameter for the enhancement of wound healing. Macrophages and multinucleated giant cells were found contiguous to the beads, but the authors doubt that they are engulfed (Figure 8).…”

Increase in wound breaking strength in rats in the presence of positively charged dextran beads correlates with an increase in endogenous transforming growth factor‐β1 and its receptor TGF‐βRI in close proximity to the wound

“…One such agent that has been recently described to accelerate the wound healing process is a positively charged microsphere, such as diethylaminoethanol (DEAE) Sephadex. 13–17 DEAE Sephadex has also been shown to accelerate wound healing in impaired models, such as the irradiated rat model. 14 Beneficial effects of DEAE Sephadex have also been shown in promoting dermal and subcutaneous augmentation, 15 and connective tissue formation in bony defects.…”

“…16 A resorbable version of DEAE‐Sephadex (R‐DEAE A25) was developed in our laboratories and was shown to increase wound tensile strength in rats and nonhuman primates following the application of a single dose of R‐DEAE A25 at the time of wound closure. 17 Histological analysis of R‐DEAE A25‐treated incisions show that the positively charged beads cluster in close proximity to the wound. The result is a highly cellular “bead pocket” in which the beads act as a biocompatible substrate for cell adhesion and proliferation.…”

“…13,15 The macrophages cluster in the “bead pocket” and remain there for at least 10 days post‐wounding. 17 Macrophages are known to be a major source of chemotactic factors that attract other inflammatory cells and mesenchymal cells. 9 It is likely that the “bead pocket” is a cellular response to the biomaterial that causes a chain of events that leads to increases in wound strength.…”