Special Issue "Drug Delivery in Regenerative Medicine"

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (30 June 2019).

Special Issue Editor

Prof. Laura B. Creemers
E-Mail Website
Guest Editor
Department of Orthopedics, University Medical Center, Heidelberglaan 100, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
Interests: biomaterials-based local delivery approaches for regeneration and treatment of inflammation

Special Issue Information

Dear Colleagues,

Delivery of instructive cues to the body is one of the instrumental pillars in regenerative medicine. Growth factors stimulating resident or exogenously added cells, or factors attracting native stem cells have shown promise in several tissues, including bone, nerve and skin tissue. Drug delivery can also help in modulating the environment of regenerating tissues e.g. small molecules inhibiting harmful factors such as proinflammatory cytokines, or by stimulating blood vessel ingrowth needed for regeneration. Usually the delivery system is applied locally, which allows for high local concentrations, saves on expensive biologicals and reduces systemic side effects. As delivery vehicles, biomaterial hydrogel and solid scaffolds or nano- and microspheres can be used either or not with targeting moieties for tissue-directed modulation in  complex environments. Challenges are still many; the lack of correlation of in vitro with in vivo release profiles, drug stability, the effect of the local biomaterial response, other local factors in vivo that cannot be mimicked in simple in vitro systems. Also the lack of understanding of optimal duration and dosage is a considerable hurdle still not taken.

This special issue invites manuscripts on any of these subjects, or others in the context of regenerative medicine and drug delivery approaches.

Prof. Laura B. Creemers
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (5 papers)

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Research

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Open AccessArticle
Extended Release Combination Antibiotic Therapy from a Bone Void Filling Putty for Treatment of Osteomyelitis
Pharmaceutics 2019, 11(11), 592; https://doi.org/10.3390/pharmaceutics11110592 - 08 Nov 2019
Abstract
In spite of advances in Total Joint Replacements (TJR), infection remains a major concern and a primary causative factor for revision surgery. Current clinical standards treat these osteomyelitis infections with antibiotic-laden poly(methyl methacrylate) (PMMA)-based cement, which has several disadvantages, including inadequate local drug [...] Read more.
In spite of advances in Total Joint Replacements (TJR), infection remains a major concern and a primary causative factor for revision surgery. Current clinical standards treat these osteomyelitis infections with antibiotic-laden poly(methyl methacrylate) (PMMA)-based cement, which has several disadvantages, including inadequate local drug release kinetics, antibiotic leaching for a prolonged period and additional surgical interventions to remove it, etc. Moreover, not all antibiotics (e.g., rifampicin, a potent antibiofilm antibiotic) are compatible with PMMA. For this reason, treatment of TJR-associated infections and related complications remains a significant concern. The objective of this study was to develop a polymer-controlled dual antibiotic-releasing bone void filler (ABVF) with an underlying osseointegrating substrate to treat TJR implant-associated biofilm infections. An ABVF putty was designed to provide sustained vancomycin and rifampicin antibiotic release for 6 weeks while concurrently providing an osseointegrating support for regrowth of lost bone. The reported ABVF showed efficient antibacterial and antibiofilm activity both in vitro and in a rat infection model where the ABVF both showed complete bacterial elimination and supported bone growth. Furthermore, in an in vivo k-wire-based biofilm infection model, the ABVF putty was also able to eliminate the biofilm infection while supporting osseointegration. The retrieved k-wire implants were also free from biofilm and bacterial burden. The ABVF putty delivering combination antibiotics demonstrated that it can be a viable treatment option for implant-related osteomyelitis and may lead to retention of the hardware while enabling single-stage surgery. Full article
(This article belongs to the Special Issue Drug Delivery in Regenerative Medicine)
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Open AccessArticle
Sustained Release from Injectable Composite Gels Loaded with Silver Nanowires Designed to Combat Bacterial Resistance in Bone Regeneration Applications
Pharmaceutics 2019, 11(3), 116; https://doi.org/10.3390/pharmaceutics11030116 - 12 Mar 2019
Cited by 3
Abstract
One-dimensional nanostructures, such as silver nanowires (AgNWs), have attracted considerable attention owing to their outstanding electrical, thermal and antimicrobial properties. However, their application in the prevention of infections linked to bone tissue regeneration intervention has not yet been explored. Here we report on [...] Read more.
One-dimensional nanostructures, such as silver nanowires (AgNWs), have attracted considerable attention owing to their outstanding electrical, thermal and antimicrobial properties. However, their application in the prevention of infections linked to bone tissue regeneration intervention has not yet been explored. Here we report on the development of an innovative scaffold prepared from chitosan, composite hydroxyapatite and AgNWs (CS-HACS-AgNWs) having both bioactive and antibacterial properties. In vitro results highlighted the antibacterial potential of AgNWs against both gram-positive and gram-negative bacteria. The CS-HACS-AgNWs composite scaffold demonstrated suitable Ca/P deposition, improved gel strength, reduced gelation time, and sustained Ag+ release within therapeutic concentrations. Antibacterial studies showed that the composite formulation was capable of inhibiting bacterial growth in suspension, and able to completely prevent biofilm formation on the scaffold in the presence of resistant strains. The hydrogels were also shown to be biocompatible, allowing cell proliferation. In summary, the developed CS-HACS-AgNWs composite hydrogels demonstrated significant potential as a scaffold material to be employed in bone regenerative medicine, as they present enhanced mechanical strength combined with the ability to allow calcium salts deposition, while efficiently decreasing the risk of infections. The results presented justify further investigations into the potential clinical applications of these materials. Full article
(This article belongs to the Special Issue Drug Delivery in Regenerative Medicine)
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Open AccessArticle
Applicability of a Modified Rat Model of Acute Arthritis for Long-Term Testing of Drug Delivery Systems
Pharmaceutics 2019, 11(2), 70; https://doi.org/10.3390/pharmaceutics11020070 - 07 Feb 2019
Cited by 2
Abstract
Episodes of inflammation and pain are predominant features of arthritic joint diseases. Drug delivery systems (DDS) could reduce inflammation and pain long-term without chances of infection upon multiple injections. To allow for long-term evaluation of DDS, we modified a previously published acute arthritis [...] Read more.
Episodes of inflammation and pain are predominant features of arthritic joint diseases. Drug delivery systems (DDS) could reduce inflammation and pain long-term without chances of infection upon multiple injections. To allow for long-term evaluation of DDS, we modified a previously published acute arthritis model by extending follow-up periods between flare-ups. Unilateral synovial inflammation of the knee was induced by intra-articular injection of streptococcal cell wall peptidoglycan polysaccharide (PGPS), and flare-ups were induced by intravenous PGPS injections every 4 weeks for a total duration of 84 days. In PGPS-reactivated animals, joint swelling, pain behavior, post mortem synovitis, and osteophyte formation were notable features. Hepatitis, splenitis and inflammation of non-primed joints were observed as systemic side effects. To test the applicability of the modified arthritis model for long-term testing of DDS, the duration of anti-inflammatory and analgesic effects of a corticosteroid released from two different polymer-based platforms was evaluated. The current modified arthritis model has good applicability for testing of DDS for a prolonged period of time. Furthermore, the novel autoregulatory polyesteramide (PEA) microsphere platform releasing triamcinolone acetonide (TAA) was benchmarked against poly lactic-co-glycolic acid (PLGA) and reduced joint swelling and pain behavior more potently compared to TAA-loaded PLGA microspheres. Full article
(This article belongs to the Special Issue Drug Delivery in Regenerative Medicine)
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Review

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Open AccessReview
Fibrin as a Multipurpose Physiological Platform for Bone Tissue Engineering and Targeted Delivery of Bioactive Compounds
Pharmaceutics 2019, 11(11), 556; https://doi.org/10.3390/pharmaceutics11110556 - 28 Oct 2019
Abstract
Although bone graft is still considered as the gold standard method, bone tissue engineering offers promising alternatives designed to mimic the extracellular matrix (ECM) and to guide bone regeneration process. In this attempt, due to their similarity to the ECM and their low [...] Read more.
Although bone graft is still considered as the gold standard method, bone tissue engineering offers promising alternatives designed to mimic the extracellular matrix (ECM) and to guide bone regeneration process. In this attempt, due to their similarity to the ECM and their low toxicity/immunogenicity properties, growing attention is paid to natural polymers. In particular, considering the early critical role of fracture hematoma for bone healing, fibrin, which constitutes blood clot, is a candidate of choice. Indeed, in addition to its physiological roles in bone healing cascade, fibrin biochemical characteristics make it suitable to be used as a multipurpose platform for bioactive agents’ delivery. Thus, taking advantage of these key assets, researchers and clinicians have the opportunity to develop composite systems that might further improve bone tissue reconstruction, and more generally prevent/treat skeletal disorders. Full article
(This article belongs to the Special Issue Drug Delivery in Regenerative Medicine)
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Open AccessReview
BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry
Pharmaceutics 2019, 11(8), 393; https://doi.org/10.3390/pharmaceutics11080393 - 05 Aug 2019
Abstract
Bone morphogenetic protein-2 (BMP-2) is a potent growth factor affecting bone formation. While recombinant human BMP-2 (rhBMP-2) has been commercially available in cases of non-union fracture and spinal fusion in orthopaedics, it has also been applied to improve bone regeneration in challenging cases [...] Read more.
Bone morphogenetic protein-2 (BMP-2) is a potent growth factor affecting bone formation. While recombinant human BMP-2 (rhBMP-2) has been commercially available in cases of non-union fracture and spinal fusion in orthopaedics, it has also been applied to improve bone regeneration in challenging cases requiring dental implant treatment. However, complications related to an initially high dosage for maintaining an effective physiological concentration at the defect site have been reported, although an effective and safe rhBMP-2 dosage for bone regeneration has not yet been determined. In contrast to protein delivery, BMP-2 gene transfer into the defect site induces BMP-2 synthesis in vivo and leads to secretion for weeks to months, depending on the vector, at a concentration of nanograms per milliliter. BMP-2 gene delivery is advantageous for bone wound healing process in terms of dosage and duration. However, safety concerns related to viral vectors are one of the hurdles that need to be overcome for gene delivery to be used in clinical practice. Recently, commercially available gene therapy has been introduced in orthopedics, and clinical trials in dentistry have been ongoing. This review examines the application of BMP-2 gene therapy for bone regeneration in the oral and maxillofacial regions and discusses future perspectives of BMP-2 gene therapy in dentistry. Full article
(This article belongs to the Special Issue Drug Delivery in Regenerative Medicine)
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