One of the main goals of materials science in the 21st century is the development of materials with rationally designed properties as substitutes for traditional pharmacotherapies. At the same time, there is a lack of understanding of the exact material properties that induce therapeutic effects in biological systems, which limits their rational optimization for the related medical applications. This study sets the foundation for a general approach for elucidating nanoparticle properties as determinants of antibacterial activity, with a particular focus on calcium phosphate nanoparticles. To that end, nine physicochemical effects were studied and a number of them were refuted, thus putting an end to frequently erred hypotheses in the literature. Rather than having one key particle property responsible for eliciting the antibacterial effect, a complex synergy of factors is shown to be at work, including (a) nanoscopic size; (b) elevated intracellular free calcium levels due to nanoparticle solubility; (c) diffusivity and favorable electrostatic properties of the nanoparticle surface, primarily low net charge and high charge density; and (d) the dynamics of perpetual exchange of ultrafine clusters across the particle/solution interface. On the positive side, this multifaceted mechanism is less prone to induce bacterial resistance to the therapy and can be a gateway to the sphere of personalized medicine. On a more problematic side, it implies a less intense effect compared to single-target molecular therapies and a difficulty of elucidating the exact mechanisms of action, while also making the rational design of theirs for this type of medical application a challenge.

1.
V. M.
Wu
,
S.
Tang
, and
V.
Uskoković
,
ACS Appl. Mater.Interfaces
10
,
34013
(
2018
).
2.
C. N.
Rochette
,
S.
Rosenfeldt
,
A.
Heiss
,
T.
Narayanan
,
M.
Ballauff
, and
W.
Jahnen-Dechent
,
ChemBioChem
10
,
735
(
2009
).
3.
L. C.
Pele
 et al,
Nanomed. Nanotechnol. Biol. Med.
13
,
619
(
2017
).
4.
J. J.
Powell
 et al,
Nat. Nanotechnol.
10
,
361
(
2015
).
5.
C.
Llena
,
L.
Forner
, and
P.
Baca
,
J. Contemp. Dent. Pract.
10
,
1
(
2009
).
6.
R. K.
Rose
,
Caries Res.
34
,
427
(
2000
).
7.
B.
Ingham
,
G. D.
Erlangga
,
A.
Smialowska
,
N. M.
Kirby
,
C.
Wang
,
L.
Matia-Merino
,
R. G.
Haverkamp
, and
A. J.
Carr
,
Soft Matter.
11
,
2723
(
2015
).
8.
J.
Zhao
,
Y.
Liu
,
W.-B.
Sun
, and
H.
Zhang
,
Chem. Cent. J.
5
,
40
(
2011
).
9.
A.
Azarpazhooh
and
H.
Limeback
,
J. Am. Dent. Assoc.
139
,
915
(
2008
).
10.
C.
Rahiotis
,
G.
Vougiouklakis
, and
G.
Eliades
,
J. Dent.
36
,
272
(
2008
).
11.
G. K.
Divyapriya
,
P. C.
Yavagal
, and
D. J.
Veeresh
,
Int. J. Oral Health Sci.
6
,
18
(
2016
).
12.
C.
Chen
,
M. D.
Weir
,
L.
Cheng
,
N. J.
Lin
,
S.
Lin-Gibson
,
L. C.
Chow
,
X.
Zhou
, and
H. H.
Xu
,
Dent Mater.
30
,
891
(
2014
).
13.
E. L.
Pearce
,
E. M.
Hancock
, and
I. H.
Gallagher
,
Arch. Oral Biol.
29
,
521
(
1984
).
14.
J.
Tanaka
,
N.
Mukai
,
M.
Tanaka
, and
M.
Tanaka
,
Int. J. Dent.
2012
,
452108
.
15.
S.
Lemaire
,
F.
Van Bambeke
,
D.
Pierard
,
P. C.
Appelbaum
, and
P. M.
Tulkens
,
Clin. Infect. Dis.
52
,
S493
(
2011
).
16.
L.-W.
Du
 et al,
Cryst. Growth Des.
13
,
3103
(
2013
).
17.
R. A.
Hirst
,
C.
Harrison
,
K.
Hirota
, and
D. G.
Lambert
, “
Measurement of [Ca2+]i in whole cell suspensions using fura-2
,” in
Methods in Molecular Biology, Vol. 312: Calcium Signaling Protocols, 2nd ed.
, edited by
D. G.
Lambert
(
Humana
,
Totowa
,
NJ
,
2005
).
18.
P. D.
Bragg
and
D. J.
Rainnie
,
Can. J. Microbiol.
20
,
883
(
1974
).
19.
Q. L.
Feng
,
J.
Wu
,
G. Q.
Chen
,
F. Z.
Cui
,
T. M.
Kim
, and
J. O.
Kim
,
J. Biomed. Mater. Res.
52
,
662
(
2000
).
20.
M.
Yamanaka
,
K.
Hara
, and
J.
Kudo
,
Appl. Environ. Microbiol.
71
,
7589
(
2005
).
21.
R.
Meena
,
K.
Kesari
,
M.
Rani
, and
R.
Paulraj
,
J. Nanoparticle Res.
14
,
1
(
2012
).
22.
A. E.
Ewence
,
M.
Bootman
,
H. L.
Roderick
,
J. N.
Skepper
,
G.
McCarthy
,
M.
Epple
,
M.
Neumann
,
C. M.
Shanahan
, and
D.
Proudfoot
,
Circ. Res.
103
,
e28
(
2008
).
23.
S. V.
Dorozhkin
,
J. Funct. Biomater.
4
,
209
(
2013
).
24.
K. J.
Thomas
III and
C. V.
Rice
,
Biometals
27
,
1361
(
2014
).
25.
Y.
Xie
and
L.
Yang
,
Sci. Rep.
6
,
20628
(
2016
).
26.
J. E.
Baik
,
K. Y.
Kum
,
C. H.
Yun
,
J. K.
Lee
,
K.
Lee
,
K. K.
Kim
, and
S. H.
Han
,
J. Endod.
34
,
1355
(
2008
).
27.
D.
Aderka
,
D.
Schwartz
,
M.
Dan
, and
Y.
Levo
,
Arch. Intern. Med.
147
,
232
(
1987
).
28.
V.
Uskoković
and
T. A.
Desai
,
J. Biomed. Mater. Res. Part A
101
,
1416
(
2013
).
29.
P.
Gangola
and
B. P.
Rosen
,
J. Biol. Chem.
262
,
12570
(
1987
).
30.
F.
Betts
,
N. C.
Blumenthal
,
A. S.
Posner
,
G. L.
Becker
, and
A. L.
Lehninger
,
Proc. Natl. Acad. Sci. U.S.A.
72
,
2088
(
1975
).
31.
R.
Naseem
,
I. B.
Holland
,
A.
Jacq
,
K. T.
Wann
, and
A. K.
Campbell
,
Biochim. Biophys. Acta Biomembr.
1778
,
1415
(
2008
).
32.
M.
Grodzik
,
E.
Sawosz
,
M.
Wierzbicki
,
P.
Orlowski
,
A.
Hotowy
,
T.
Niemiec
,
M.
Szmidt
,
K.
Mitura
, and
A.
Chwalibog
,
Int. J. Nanomed.
6
,
3041
(
2011
).
33.
C. A.
Orme
and
J. L.
Giocondi
, “
The use of scanning probe microscopy to investigate crystal-fluid interfaces
,” in
Perspectives on Inorganic, Organic, and Biological Crystal Growth from Fundamentals to Applications
, edited by
M.
Skowronski
,
J. J.
DeYoreo
, and
C. A.
Wang
(
American Institute of Physics
,
Melville
,
NY
,
2007
).
34.
A.
Carino
,
C.
Ludwig
,
A.
Cervellino
,
E.
Müller
, and
A.
Testino
,
Acta Biomater.
74
,
478
(
2018
).
35.
D. I.
Andresson
,
D.
Hughes
, and
J. Z.
Kubicek-Sutherland
,
Drug Resist. Updates
26
,
43
(
2016
).
36.
A. M.
Carmona-Ribeiro
and
L. D.
de Melo Carrasco
,
Int. J. Mol. Sci.
14
,
9906
(
2013
).
37.
X. L.
Fan
 et al,
ACS Appl. Mater. Interfaces
10
,
10428
(
2018
).
38.
S.
Jiang
and
Z.
Cao
,
Adv. Mater.
22
,
920
(
2010
).
39.
M.
He
 et al,
Acta Biomater.
40
,
142
(
2016
).
40.
V.
Uskoković
and
T. A.
Desai
,
ACS Appl. Mater.Interfaces
6
,
13209
(
2014
).
41.
V.
Uskoković
,
Z.
Castiglione
,
P.
Cubas
,
L.
Zhu
,
W.
Li
, and
S.
Habelitz
,
J. Den. Res.
89
,
149
(
2010
).
42.
L.
Gritsch
,
C.
Lovell
,
W. H.
Goldmann
, and
A. R.
Boccaccini
,
J. Mater. Sci. Mater. Med.
29
,
18
(
2018
).
43.
L.
Tronstad
,
J. O.
Andreasen
,
G.
Hasselgren
,
L.
Kristerson
, and
I.
Riis
,
J. Endod.
7
,
17
(
1981
).
44.
V.
Uskoković
,
J. Biomed. Nanotechnol.
9
,
1441
(
2013
).
45.
S.
Hirn
 et al,
Eur. J. Pharm. Biopharm.
77
,
407
(
2011
).
46.
J. R.
Morones
,
J. L.
Elechiguerra
,
A.
Camacho
,
K.
Holt
,
J. B.
Kouri
, and
J. T.
Ramirez
,
Nanotechnology
16
,
2346
(
2005
).
47.
L. S.
Taylor
and
G. G. Z.
Zhang
,
Adv. Drug Deliv. Rev.
101
,
122
(
2016
).
48.
P. J.
ter Brugger
,
J. G.
Wolke
, and
J. A.
Jansen
,
J. Biomed. Mater. Res.
60
,
70
(
2002
).
49.
E.
Vella
,
F.
Messina
,
M.
Cannas
, and
R.
Boscaino
,
Phys. Rev. B
83
,
174201
(
2011
).
50.
C.
Zhang
,
J.
Yang
,
Z.
Quan
,
P.
Yang
,
C.
Li
,
Z.
Hou
, and
J.
Lin
,
Cryst. Growth Des.
9
,
2725
(
2009
).
51.
C.
Zhang
,
C.
Li
,
S.
Huang
,
Z.
Hou
,
Z.
Cheng
,
P.
Yang
,
C.
Peng
, and
J.
Lin
,
Biomaterials
31
,
3374
(
2010
).
52.
C.
Wang
,
D.
Liu
,
C.
Zhang
,
J.
Sun
,
W.
Feng
,
X. J.
Liang
,
S.
Wang
, and
J.
Zhang
,
ACS Appl. Mater. Interfaces
8
,
11262
(
2016
).
53.
R. K.
Singh
,
T.-H.
Kim
,
K. D.
Patel
,
J.-J.
Kim
, and
H.-W.
Kim
,
J. Mater Chem. B
2
,
2039
(
2014
).
54.
S.
Valizadeh
,
M. H.
Rasoulifard
, and
M. S. S.
Dorraji
,
Korean J. Chem. Eng.
33
,
481
(
2016
).
55.
S.
Rehman
,
R.
Ullah
,
A. M.
Butt
, and
N. D.
Gohar
,
J. Hazardous Mater.
170
,
560
(
2009
).
56.
T.
Bak
,
J.
Nowotny
,
M.
Rekas
, and
C. C.
Sorrell
,
Int. J. Hydrogen Energy
27
,
991
(
2002
).
57.
L.
Cheng
,
M. D.
Weir
,
H. H.
Xu
,
J. M.
Antonucci
,
N. J.
Lin
,
S.
Lin-Gibson
,
S. M.
Xu
, and
X.
Zhou
,
J. Biomed. Mater. Res. B Appl. Biomater.
100
,
1378
(
2012
).
58.
F.
Nudelman
,
K.
Pieterse
,
A.
George
,
P. H. H.
Bomans
,
H.
Friedrich
,
L. J.
Brylka
,
P. A. J.
Hilbers
,
G.
de With
, and
N. A. J. M.
Sommerdijk
,
Nat. Mater.
9
,
1004
(
2010
).
59.
M. M.
Kłosowski
,
R.
Carzaniga
,
S. J.
Shefelbine
,
A. E.
Porter
, and
D. W.
McComb
,
Sci. Rep.
8
,
3024
(
2018
).
60.
V.
Uskoković
,
S.
Marković
,
L. J.
Veselinović
,
S.
Škapin
,
N.
Ignjatović
, and
D. P.
Uskoković
,
Phys. Chem. Chem. Phys.
20
,
29221
(
2018
).
61.
A.
Dey
,
P. H.
Bomans
,
F. A.
Müller
,
J.
Will
,
P. M.
Frederik
,
G.
de With
, and
N. A.
Sommerdijk
,
Nat. Mater.
9
,
1010
(
2010
).
62.
B.
Xie
,
T. J.
Halter
,
B. M.
Borah
, and
G. H.
Nancollas
,
Cryst. Growth Des.
14
,
1659
(
2014
).
63.
B.
Wopenka
and
J. D.
Pasteris
,
Mater. Sci. Eng. C
25
,
131
(
2005
).
64.
C.
Rey
,
C.
Combes
,
C.
Drouet
, and
M. J.
Glimcher
,
Osteoporos. Int.
20
,
1013
(
2009
).
65.
R. A.
Harper
and
A. S.
Posner
,
Proc. Soc. Exp. Biol. Med.
122
,
137
(
1966
).
66.
S.
Jiang
,
H.
Pan
,
Y.
Chen
,
X.
Xu
, and
R.
Tang
,
Faraday Discuss.
179
,
451
(
2015
).
67.
V.
Uskoković
and
T. A.
Desai
,
J. Pharm. Sci.
103
,
567
(
2014
).
68.
S.
Jiang
,
Y.
Chen
,
H.
Pan
,
Y. J.
Zhan
, and
R.
Tang
,
Phys. Chem. Chem. Phys.
15
,
12530
(
2013
).
69.
V.
Uskoković
,
S.
Tang
, and
V. M.
Wu
,
ACS Appl. Mater. Interfaces
10
,
14491
(
2018
).
70.
H.
Fleisch
,
Clin. Orthop.
32
,
170
(
1964
).
71.
E. D.
Eanes
and
A. S.
Posner
, “
Structure and chemistry of bone mineral
,” in
Biological Calcification Cellular and Molecular Aspects
, edited by
H.
Schraer
(
Appleton-Centyr Crofts
,
New York
,
NY
,
1970
), pp.
1
26
.
72.
H.
Cölfen
,
Nature
9
,
960
(
2010
).
73.
W.
Li
,
J.
Zhu
, and
Z.
Mou
,
Petroleum Sci.
4
,
75
(
2007
).
74.
C. A.
Orme
and
J. L.
Giocondi
, “
The use of scanning probe microscopy to investigate crystal-fluid interfaces
,” in
Perspectives on Inorganic, Organic, and Biological Crystal Growth from Fundamentals to Applications
, edited by
M.
Skowronski
,
J. J.
DeYoreo
, and
C. A.
Wang
(
American Institute of Physics
,
Melville
,
NY
,
2007
).
75.
V.
Uskoković
,
W.
Li
, and
S.
Habelitz
,
J. Bionic Eng.
8
,
114
(
2011
).
76.
A.
Filankembo
,
S.
Giorgio
,
I.
Lisiecki
, and
M. P.
Pileni
,
J. Phys. Chem. B
107
,
7492
(
2003
).
77.
L.
Wang
and
W.
Colon
,
Biochemistry
46
,
5562
(
2007
).
78.
79.
A. F.
Gualtieri
,
Toxicol. Appl. Pharmacol.
361
,
89
(
2018
).
80.
C.
Kinnear
,
T. L.
Moore
,
L.
Rodriguez-Lorenzo
,
B.
Rothen-Rutishauser
, and
A.
Petri-Fink
,
Chem. Rev.
117
,
11476
(
2017
).
81.
V.
Uskoković
,
S. S.
Batarni
,
J.
Schweicher
,
A.
King
, and
T. A.
Desai
,
ACS Appl. Mater. Interfaces
5
,
2422
(
2013
).
82.
G.
Bateson
,
Mind and Nature: A Necessary Unity
(
Hampton
,
Cresskill
,
NJ
,
1979
), p.
199
.
83.
P. N.
Lim
,
L.
Chang
, and
E. S.
Thian
,
Nanomed. Nanotechnol. Biol. Med.
11
,
1331
(
2015
).
You do not currently have access to this content.