MICRO-AND NANOSPHERES FOR TISSUE ENGINEERING - Micro and Nanotechnologies in Engineering Stem Cells and Tissues - page 209

injectable 3D constructs that can encapsulate MSCs in which -TCP microspheres of

high stiffness reinforced the mechanical strength of the alginate matrix. 15 On the
other hand, micro- and nanospheres embedded into the continuous phase of bio-
materials can also act as cross-linking anchors to form direct bridges between micro-
and nanospheres with the surrounding network or function as delivery vehicles that
encapsulate cross-linking agents and subsequently release them to trigger cross-
linking of the surrounding polymer phase. For instance, positively charged PLA
microspheres were embedded in an anionic polymer phase of hyaluronic acid to
induce gelation of hyaluronic acid by forming polyion complexes without introduc-
ing cross-linking chemicals that can be cytotoxic. 16 Moreover, in the design of
so-called self-healing biomaterials, microspheres can be used as microcapsules
containing an active healing agent dispersed in a polymer matrix. When a propagat-
ing crack encounters a microcapsule and causes its rupture, the healing agent is
released to initiate a repolymerization process, thus filling the crack area. 83 This
approach of using microspheres in designing self-healing biomaterials is an excit-
ingly new area that can be of great benefit in the development of novel biomaterials.

b

9.3.3 Micro- and Nanospheres as Microreactors

Hollow micro- and nanospheres (microcapsules) have been investigated recently for
their potential to serve as microscopic bioreactors for dedicated biochemical
processes in biomedical applications. 17,84,85 Candidates for this purpose include
polymeric capsules, liposomes, polymersomes, and so on that can (1) create a inner
compartment capable of efficient entrapment of components of interest; (2) provide a
sufficiently robust and stable shell, allowing for selective diffusion of substrate
components or reaction products into or out of the capsules; and (3) introduce no
harmful effect to native cells and tissues. 85,86
A representative example of using microcapsules for biomedical applications is
the controlled formation of biominerals in defined compartments. This strategy is
inspired by the process of endochondral bone formation that uses nanosized matrix
vesicles as initial sites of biomineralization. 17,18 To this end, Michel et al. developed
an approach using liposomes encapsulated with calcium ions and alkaline phospha-
tase (the enzyme that releases inorganic phosphate ions from organic phosphate
esters in vivo) to induce CaP crystals formation under well-controlled conditions
(Fig. 9.3). 87 Similarly, Pederson et al. developed calcium- and phosphate-loaded
liposomes in combination with collagen hydrogels, which facilitated in situ forma-
tion of CaP crystals and subsequent mineralization of hydrogels, and finally formed
self-hardening biomaterials that can be applied as injectable, self-gelling formula-
tions for bone regeneration. 17 Another biomimetic approach for inducing biomineral
formation inside polyelectrolyte capsules was developed by Antipov et al. 88 based on
urease-catalyzed precipitation of carbonate in the capsule interior. By suspending
urease-loaded capsules in aqueous solutions containing CaCl 2 and urea, CaCO 3
mineralization was triggered because of the impermeability of urease macromole-
cules inside the capsules, but high permeability of small urea molecules and Ca 2 þ
through the capsule wall allowed for precipitation of inorganic crystals. These