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Review
. 2020 May 6;12(5):428.
doi: 10.3390/pharmaceutics12050428.

Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches

Rebecca Rothe  1   2 , Sandra Hauser  1 , Christin Neuber  1 , Markus Laube  1 , Sabine Schulze  3   4 , Stefan Rammelt  3   4   5 , Jens Pietzsch  1   2
Affiliations
Review

Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches

Rebecca Rothe et al. Pharmaceutics. .

Abstract

Bone defects of critical size after compound fractures, infections, or tumor resections are a challenge in treatment. Particularly, this applies to bone defects in patients with impaired bone healing due to frequently occurring metabolic diseases (above all diabetes mellitus and osteoporosis), chronic inflammation, and cancer. Adjuvant therapeutic agents such as recombinant growth factors, lipid mediators, antibiotics, antiphlogistics, and proangiogenics as well as other promising anti-resorptive and anabolic molecules contribute to improving bone healing in these disorders, especially when they are released in a targeted and controlled manner during crucial bone healing phases. In this regard, the development of smart biocompatible and biostable polymers such as implant coatings, scaffolds, or particle-based materials for drug release is crucial. Innovative chemical, physico- and biochemical approaches for controlled tailor-made degradation or the stimulus-responsive release of substances from these materials, and more, are advantageous. In this review, we discuss current developments, progress, but also pitfalls and setbacks of such approaches in supporting or controlling bone healing. The focus is on the critical evaluation of recent preclinical studies investigating different carrier systems, dual- or co-delivery systems as well as triggered- or targeted delivery systems for release of a panoply of drugs.

Keywords: angiogenesis; bioactive scaffolds; bone grafting; critical-size bone defects; drugs; inflammation; osseointegration; osteoconduction; osteoinduction; tissue regeneration.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no influence on the conception of the review, interpretation of literature data, conclusions drawn, or in the decision to publish this review.

Figures

Figure 1
Figure 1
Exemplary schematic drug release kinetics for single and dual drug delivery.
Figure 2
Figure 2
Chemical structures of selected anti-resorptive bisphosphonates. Bisphosphonates improve the bone quality due to accelerated bone mineralization and are frequently used in the treatment of osteoporosis. The hydrophilic molecules contain the typical P–C–P core structure and exhibit a high binding affinity to bone minerals.
Figure 3
Figure 3
Chemical structures of selected HMG-CoA reductase inhibitors. The statins elicit pleiotropic effects regarding bone regeneration, despite having different carbo- and heterocyclic core structures. Anabolic impacts rely on stimulation of osteogenesis, but the statins also evoke dose-dependent anti-inflammatory and pro-angiogenic effects.
Figure 4
Figure 4
Exemplary scaffold formulations for bone-targeted drug delivery.
Figure 5
Figure 5
Chemical structures of sphingosine 1-phosphate receptor agonists. The lipid mediators act mainly on vascularization and bone metabolic cells.
Figure 6
Figure 6
Chemical structure of selected enzyme inhibitors. GSK-3ß is a key enzyme of the Wnt/ß-catenin pathway and inhibition results in cytosolic accumulation of ß-catenin and further transcription of target genes promoting bone formation. Proteasome inhibitor bortezomib, mainly used in treatment of multiple myeloma, hinders proteasomal degradation of ß-catenin leading to the effects mentioned above. Furthermore, phosphodiesterase-4 inhibitors are anti-inflammatory agents and stimulate cellular proliferation as well as differentiation due to accumulated cGMP (cyclic guanosine monophosphate) and protein kinase G-mediated downstream signaling.
Figure 7
Figure 7
Exemplary drug loading techniques for simultaneous or sequential drug co-delivery.
Figure 8
Figure 8
Chemical structures of selected anti-inflammatory drugs. Both glucocorticoids and NSAIDs are inflammation-modulatory small molecules inhibiting cyclooxygenase isoforms and prostaglandin production. These drugs mainly impair bone repair, as prostaglandins are crucial during early bone healing phases.
Figure 9
Figure 9
Chemical structures of selected antibiotics. Gentamicin prevents bone infections, whereas tetracycline inhibits osteoclast differentiation and displays a high affinity to bone minerals as well.
Figure 10
Figure 10
Exemplary targeted drug delivery approaches based on internal or external stimuli.
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