**4. Conclusions**

The intended drug delivery system that this study sought to develop was one that could provide sustained zero-order release of nicotine from a crosslinked polyspheric system. This would allow for the attainment of constant drug levels at the site of action and minimize adverse effects associated with fluctuating drug levels, as well as optimizing patient therapy and compliance. PLGA matrices incorporating calcium barium-crosslinked alginate-hydroxyethylcellulose gelispheres offered minimal rates of matrix degradation and successfully retarded nicotine release, leading to the achieved zero-order release for 50 days following exposure to simulated CSF. The computational modeling methods that were used for the prediction of preferred molecular conformations of the drug–polymer and polymer-polymer complexes using force field minimizations and the modes of interaction corroborated well the experimental results. The developed drug delivery system displays a grea<sup>t</sup> potential for use in the treatment of Parkinson's disease.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/10/4/233/s1, Figure S1: Image processing of micrograph of a PLGA scaffold: (**a**) BLURimage: blurred SEMimage; (**b**) CQimage: colorquantized image of BLURimage; (**c**) UniHisto: uniform histogram of CQimage; (**d**) UniHistoSep: separated uniform histogram of CQimage after image processing; (**e**) NonUniHisto: non-uniform histogram of SEMimage before image processing; and (**f**) NonUniHistoSep: separated non-uniform histogram of SEMimage before image processing. Note that each color channel is only capable of highlighting most of the pores, but not all.

**Author Contributions:** Conceptualization, Y.E.C. and V.P.; Methodology, P.K., L.D.d.T. and N.S.; Software, P.K.; Formal Analysis, P.K. and N.S.; Resources, V.P.; Writing—Original Draft Preparation, P.K.; Writing—Review & Editing, all authors; Supervision, Y.E.C. and V.P.; Funding Acquisition, V.P.

**Funding:** This work was funded by the National Research Foundation (NRF) of South Africa.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
