**7. Other Alginate-Based Dressings**

Among the alginate-based wound healing blends (Table 4) are gelatin-alginate sponges, alginate-scaffolds based on antisense oligo-deoxynucleotides (asODN) linking to Connexin 43 (Cx43) [11,104], viscose/Ag NPs/ALG/nicotinamide/CaCl<sup>2</sup> fabrics [105]. The 3D bi-layered scaffold made of polyethylene glycol (PEG)-chitosan hydrogel and chitosanalginate can also help tissue regeneration after injury by holding fibroblasts on the upper surface and keratinocytes on the lower one [106,107].

The wound pH is a reliable factor when discussion the healing status, because it shifts from high when infected to low when healed either naturally or because it was modulated through applying different treatments [108–110]. Polyethylene oxide–alginate wafers loaded with diclofenac and streptomycin show controlled drug release at room temperature, in simulated wound fluid (BSA, CaCl2, NaCl, C4H11NO3) conditions at pH 7.5. The diffusion of both drugs from the annealed wafers takes place slowly, making them potentially useful in highly exuding wounds [23,111]. Because wound pH-variation has a strong effect on the healing process, researchers also developed, through microfluidic spinning using their electrostatic interactions, a mesoporous particle hydrogel alginatebased flexible microfiber linked to a pH-responsive dye linked onto a transparent medical tape place on top of a wound, in order to observe the pH modifications in real-time [112].

A 3D porous sponge was obtained after a pre-gelled (with bivalent cations) alginate was frozen and then lyophilized. The type and concentration of both alginate and crosslinkers, as well as the freezing protocol influenced the mechanical properties as well as the size (70–300 µm) and display pattern of the pores. This pore size was appropriate for fibroblast seeding [113]. On the other hand, when comparing the tensile strength for G-ALG and M-ALG sponge dressings with different ALG concentrations, the elongation at fracture was not influenced by the alginate concentration, whereas Young's modulus and the maximum stress at fracture increased with it [114].


**Table 4.** Other alginate-based dressings used for wound healing.


**Table 4.** *Cont.*

PEG addition to the aforementioned sponge increases the flexibility while having a plasticizing effect. Furthermore, its concentration and molecular weight significantly modifies the tensile strength of the sponge. For low molecular weight PEG of 1.45 kDa a concentration increases from 0.1% to 1% leads to a lower Young's modulus, maximum stress at fracture and elongation at fracture. For high molecular weight PEG (10 kDa) the concentration increases from 0.1% to 1% leads to an increase for Young's modulus and maximum stress at fracture, while the elongation at fracture is significantly lower. While comparing the results between the uses of different molecular weight PEG in the sponge, the one with a molecular weight of 1.45 kDa displayed higher tensile strength values than the 10 kDa PEG. PEG addition to the M-ALG sponges also increases the WVTR and decreases the water absorption capacity, regardless of its molecular weight, but the observed values for WVTR (16.7 ± 0.4 before PEG addition and (22.9 ± 0.8)–(28.8 ± 2.1) after PEG addition) were almost double the recommended values (8–10 mg/cm2/h) [114].

#### **8. Commercially Available Pharmaceutical Alginate-Based Products**

The list of commercially available alginate-based wound dressing is growing fast (Table 5), while the most recent FDA approval available on-line at this time was given to Luofucon® Extra Silver Alginate Dressing (Prescribed only—PO) and Luofucon® Antibacterial Alginate Wound Dressing (Over-The-Counter—OTC) [126,127]. The researchers state the dressings proved their activity against *E. coli*, *E. faecalis*, *K. pneumoniae*, Methicillinresistant *S. aureus* (MRSA), *P. aeruginosa*, *S. aureus*, *S. pyogenes*, and Vancomycin-resistant *Enterococcus* (VRE). Silver creates a barrier against a broad spectrum of bacteria [128] for as long as seven days [126].

Enzymes were added into a PEG-alginate hydrogel called Flaminal® Forte that underwent human clinical trials for treating partial thickness burns [129] and had better results than the Ag sulfadiazine-based one (Flamazine®), regarding the times it needed to be changed [130]. When a patient is unable to move, pressure ulcers may appear. Such a case was also healed after several dressings were applied, including a honey-loaded alginatebased product, named Algivon® [131,132]. An improved version of this dressing, Algivon® Plus, showed good clinical results when applied on chronic wounds [133]. Algivon® Ribbon or Plus is also used for diabetic, pressure, and leg ulcers, fungating lesions, infected, cavity, and chronic or complicated surgical wounds and abrasions [32,131,133–136]. On the other hand, another Manuka honey loaded calcium alginate-based wound dressing is Activon® Tube or Tulle for diabetic and leg ulcers, pressure sores, and malodorous, infected, dry, sloughy, or necrotic wounds [135,137–139].

Recently, researchers have studied the effect of treating human skin lesions, produced by an atypical form of Henoch–Shönlein purpura, with three hyaluronic acid-based commercially available products Hyalomatrix PA® (a 3D matrix of a hyaluronic acid ester

(Hyaff) and a transparent film), Hyalogran®, and Jaloskin®, which were maintained on the wound site for various time periods in a consecutive order. One of the treatments, Hyalogran®, was an alginate-hyaluronan dressing made of sodium alginate and Hyaff [140]. After the eschar resection, wound debridement, and 21 days of the first dressing, the next step was applying the second one for two weeks, and the third for an unmentioned period. After two months from the first treatment the wound was completely healed [140], with minimal scaring and thus confirming the benefits of wound treatments involving hyaluronic acid in combination with sodium alginate. Silvercel®, another commercially available alginate-based non-adherent dressing, was used in a wound healing study, when it was applied twice a week on a diabetic patient with a repetitive non-infected venous leg ulcer and the wound healed in 14 day [141].

**Table 5.** Alginate-based commercially available pharmaceutical products used in wound healing.



**Table 5.** *Cont.*

Other commercially available dressings contain both ALG and silver, like Aquacel™ Ag EXTRA™ Hydrofiber™ or ALGS6 Ag Alginate Wound Dressing have similar wound healing characteristics [142]. Various other commercially available alginate-based dressings that were included in a multiple comparative studies were Suprasorb® A (100% ALG), Suprasorb® A—Ag (ALG—ionic Ag), and LG—nano Ag ® Acticoat Absorbent with SILCRYST™, for their anti-microbial effect, binding to elastase capacity, MMP-2, TNF-α and IL-8, antioxidant ability, cytotoxicity, and effect on HaCaT keratinocytes, showing promising results [42,163,164].

#### **9. Conclusions**

The development of alginate-based biomaterials for wound healing has an accelerated pace. The last years gave patients hopes for receiving better treatment for their wounds because the development of a wound dressing that might actually become a true 'ideal dressing' seems to be in hands reach. The versatility of alginate-based wound dressings, the promising results after both in vivo and in vitro trials and the cost-effectiveness of obtaining them makes alginate one of the favorites when choosing the material that could act both as a support and as a carrier for the bio-active compounds that have to reach a wound.

**Author Contributions:** Conceptualization, A.B. and B.N.; Methodology, A.B. and B.N.; Formal analysis A.B. and B.N.; Investigation, A.B. and B.N.; Resources, A.B.; Data curation, A.B. and B.N.; Writing—original draft preparation, A.B., B.N., M.Z., G.M.I., C.B. and V.M.; Writing—review and

editing A.B., B.N., M.Z., G.M.I., C.B. and V.M.; Visualization, A.B. and B.N.; Supervision, V.M.; Project administration, A.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Acknowledgments:** This work has been conducted in the Pediatric Clinical Hospital Sibiu, within the Research and Telemedicine Center in Neurological Diseases in Children—CEFORATEN. This study is part of the doctoral thesis of the Andreea Barbu, under the supervision of Vioara Mires, an.

**Conflicts of Interest:** The authors declare no conflict of interest.
