Drug Release: Proper Control to Help Clinical Application

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Burdetee et al1 have reported results of their study on the use of amnion-derived multipotent progenitor cells secretome which they called “secretome biotherapeutic.” Proliferation of mesenchymal stem cells and osteoprogenitor cells, as well as increased migration of mesenchymal stem cells in vitro, were observed. Improvement in new bone formation and quality in rat-treated experimental calvarial critical bone defects was also seen. Secretome was combined with a collagen sponge and this was associated with burst release which might be the reason behind the lack of complete defect healing.
The secretome contains several growth factors which likely influence proliferation and migration such as platelet-derived growth factor BB, transforming growth factor beta 2, vascular endothelial growth factor, tissue inhibitor of metalloproteinases 1, tissue inhibitor of metalloproteinases 2 and angiogenin.2
It was commented that the amount of used secretome may not have been enough to result in full healing of treated experimental rat critical size bone defects. However, other reasons might be the main player. Burst release results in freeing of ∼50% of loaded secretome leaving the other 50% to be released over the following period of 14 days at subtherapeutic suboptimal level (Fig. 1). New ideas to develop more and smarter controlled release systems are needed, to improve outcome and may help in clinical translation.
While collagen has been used previously for release of growth factors, it may not have necessarily been optimal carrier. It was noticed that increased amounts of growth factors may be needed to achieve effect on bone healing. However, increased dose may lead to adverse effects some of which may not be known and, thus pose concerns. With high dose of BMP2 for example, inflammatory infiltrate and increased number of osteoclast-like cells were seen.3 Increasing dose leads also to raising cost. Together, these factors hinder clinical application. Growth factors are acting in concert and precisely controlled in both spatial and temporal fashions. Such properties should be integrated into drug release system to achieve good results.
To achieve good control over drug release meeting required therapeutic levels, various biomaterials and manufacturing techniques were previously used by our team and collaborators, e.g., those for antibiotic,4–7 anti-inflammatory drugs such as diclofenac8 and dexamethasone,9 or anti-osteolytic agent10 releasing devices. Control of drug release was developed by using various methods including building of temporally controlled multicomponent implant (melt extruded, self-reinforced, and sterilized components11), multilayered implant with various degrading and drug-releasing profiles, and implant containing several drugs (diclofenac, dexamethasone, and clodronate12), and anti-inflammatory releasing nanofibers from various polymers13,14 including pH responsive polymers.15
Used polymers such as poly(lactide-co-glycolide) need relatively high temperatures and, hence heat-sensitive molecules such as growth factors can be damaged. Using solvents, cytotoxicity may be encountered. A cold process using other methods can be of use for example electrospinning. It was possible to successfully load albumin (as a model for polypeptide molecules) into electrospun poly(vinyl alcohol) nanofibers16 or combine it in a multicomponent construct with anti-inflammatory agent.17
There are several successful works from different groups. It is worth combining such an important material such as amnion-derived multipotent progenitor cell secretome with proper releasing system and investigate this further so it can be closer to cost-effective, clinically feasible, and successful application.
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