Posts Tagged ‘therapies’

Reporter Aviral Vatsa, PhD MBBS

Annual treatment costs for musculoskeletal diseases in the US are roughly 7.7% (~ $849 billion) of total gross domestic product. Such disorders are the main cause of physical disability in US. Almost half of all chronic conditions in people can be attributed to bone and joint disorders. In addition there is increasing ageing population and associated increases in osteoporosis and other diseases, rising incidences of degenerative intervertebral disk diseases and numbers of revision orthopedic arthroplasty surgeries, and increases in spinal fusions. All these factors contribute towards the increasing requirement of bone regeneration and reconstruction methods and products. Delivery of therapeutic grade products to bone has various challenges. Parenteral administration limits the efficient delivery of drugs to the required site of injury and local delivery methods are often expensive and invasive. The theme issue of Advance Drug Delivery reviews focuses on the current status of drug delivery to bone and the issues facing this field. Here is the first part of these reviews and research articles.

1. Demineralized bone matrix in bone repair: History and use


Demineralized bone matrix (DBM) is an osteoconductive and osteoinductive commercial biomaterial and approved medical device used in bone defects with a long track record of clinical use in diverse forms. True to its name and as an acid-extracted organic matrix from human bone sources, DBM retains much of the proteinaceous components native to bone, with small amounts of calcium-based solids, inorganic phosphates and some trace cell debris. Many of DBM’s proteinaceous components (e.g., growth factors) are known to be potent osteogenic agents. Commercially sourced as putty, paste, sheets and flexible pieces, DBM provides a degradable matrix facilitating endogenous release of these compounds to the bone wound sites where it is surgically placed to fill bone defects, inducing new bone formation and accelerating healing. Given DBM’s long clinical track record and commercial accessibility in standard forms and sources, opportunities to further develop and validate DBM as a versatile bone biomaterial in orthopedic repair and regenerative medicine contexts are attractive.

2. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration


The regeneration of large bone defects caused by trauma or disease remains a significant clinical problem. Although osteoinductive growth factors such as bone morphogenetic proteins have entered clinics, transplantation of autologous bone remains the gold standard to treat bone defects. The effective treatment of bone defects by protein therapeutics in humans requires quantities that exceed the physiological doses by several orders of magnitude. This not only results in very high treatment costs but also bears considerable risks for adverse side effects. These issues have motivated the development of biomaterials technologies allowing to better control biomolecule delivery from the solid phase. Here we review recent approaches to immobilize biomolecules by affinity binding or by covalent grafting to biomaterial matrices. We focus on biomaterials concepts that are inspired by extracellular matrix (ECM) biology and in particular the dynamic interaction of growth factors with the ECM. We highlight the value of synthetic, ECM-mimicking matrices for future technologies to study bone biology and develop the next generation of ‘smart’ implants.


3. Calcium phosphate cements as drug delivery materials


Calcium phosphate cements are used as synthetic bone grafts, with several advantages, such as their osteoconductivity and injectability. Moreover, their low-temperature setting reaction and intrinsic porosity allow for the incorporation of drugs and active principles in the material. It is the aim of the present work to: a) provide an overview of the different approaches taken in the application of calcium phosphate cements for drug delivery in the skeletal system, and b) identify the most significant achievements. The drugs or active principles associated to calcium phosphate cements are classified in three groups, i) low molecular weight drugs; ii) high molecular weight biomolecules; and iii) ions.

4. Silk constructs for delivery of musculoskeletal therapeutics


Silk fibroin (SF) is a biopolymer with distinguishing features from many other bio- as well as synthetic polymers. From a biomechanical and drug delivery perspective, SF combines remarkable versatility for scaffolding (solid implants, hydrogels, threads, solutions), with advanced mechanical properties and good stabilization and controlled delivery of entrapped protein and small molecule drugs, respectively. It is this combination of mechanical and pharmaceutical features which renders SF so exciting for biomedical applications. This pattern along with the versatility of this biopolymer has been translated into progress for musculoskeletal applications. We review the use and potential of silk fibroin for systemic and localized delivery of therapeutics in diseases affecting the musculoskeletal system. We also present future directions for this biopolymer as well as the necessary research and development steps for their achievement.

5. Demineralized bone matrix as a vehicle for delivering endogenous and exogenous therapeutics in bone repair


As a unique human bone extract approved for implant use, demineralized bone matrix (DBM) retains substantial amounts of endogenous osteoconductive and osteoinductive proteins. Commercial preparations of DBM represent a clinically accessible, familiar, widely used and degradable bone-filling device, available in composite solid, strip/piece, and semi-solid paste forms. Surgically placed and/or injected, DBM releases its constituent compounds to bone sites with some evidence for inducing new bone formation and accelerating healing. Significantly, DBM also has preclinical history as a drug carrier by direct loading and delivery of several important classes of therapeutics. Exogenous bioactive agents, including small molecule drugs, protein and peptide drugs, nucleic acid drugs and transgenes and therapeutic cells have been formulated within DBM and released to bone sites to enhance DBM’s intrinsic biological activity. Local release of these agents from DBM directly to surgical sites in bone provides improved control of dosing and targeting of both endogenous and exogenous bioactivity in the context of bone healing using a clinically familiar product. Given DBM’s long clinical track record and commercial accessibility in standard forms and sources, opportunities to formulate DBM as a versatile matrix to deliver therapeutic agents locally to bone sites in orthopedic repair and regenerative medicine contexts are attractive.

6. Nanofiber-based delivery of bioactive agents and stem cells to bone sites


Biodegradable nanofibers are important scaffolding materials for bone regeneration. In this paper, the basic concepts and recent advances of self-assembly, electrospinning and thermally induced phase separation techniques that are widely used to generate nanofibrous scaffolds are reviewed. In addition, surface functionalization and bioactive factor delivery within these nanofibrous scaffolds to enhance bone regeneration are also discussed. Moreover, recent progresses in applying these nanofiber-based scaffolds to deliver stem cells for bone regeneration are presented. Along with the significant advances, challenges and obstacles in the field as well as the future perspective are discussed.

7. Intra-operatively customized implant coating strategies for local and controlled drug delivery to bone


Bone is one of the few tissues in the human body with high endogenous healing capacity. However, failure of the healing process presents a significant clinical challenge; it is a tremendous burden for the individual and has related health and economic consequences. To overcome such healing deficits, various concepts for a local drug delivery to bone have been developed during the last decades. However, in many cases these concepts do not meet the specific requirements of either surgeons who must use these strategies or individual patients who might benefit from them. We describe currently available methods for local drug delivery and their limitations in therapy. Various solutions for drug delivery to bone focusing on clinical applications and intra-operative constraints are discussed and drug delivery by implant coating is highlighted. Finally, a new set of design and performance requirements for intra-operatively customized implant coatings for controlled drug delivery is proposed. In the future, these requirements may improve approaches for local and intra-operative treatment of patients.

8. Local delivery of small and large biomolecules in craniomaxillofacial bone


Current state of the art reconstruction of bony defects in the craniomaxillofacial (CMF) area involves transplantation of autogenous or allogenous bone grafts. However, the inherent drawbacks of this approach strongly urge clinicians and researchers to explore alternative treatment options. Currently, a wide interest exists in local delivery of biomolecules from synthetic biomaterials for CMF bone regeneration, in which small biomolecules are rapidly emerging in recent years as an interesting adjunct for upgrading the clinical treatment of CMF bone regeneration under compromised healing conditions. This review highlights recent advances in the local delivery small and large biomolecules for the clinical treatment of CMF bone defects. Further, it provides a perspective on the efficacy of biomolecule delivery in CMF bone regeneration by reviewing presently available reports of pre-clinical studies using various animal models.

9. Immobilized antibiotics to prevent orthopaedic implant infections


Many surgical procedures require the placement of an inert or tissue-derived implant deep within the body cavity. While the majority of these implants do not become colonized by bacteria, a small percentage develops a biofilm layer that harbors invasive microorganisms. In orthopaedic surgery, unresolved periprosthetic infections can lead to implant loosening, arthrodeses, amputations and sometimes death. The focus of this review is to describe development of an implant in which an antibiotic tethered to the metal surface is used to prevent bacterial colonization and biofilm formation. Building on well-established chemical syntheses, studies show that antibiotics can be linked to titanium through a self-assembled monolayer of siloxy amines. The stable metal–antibiotic construct resists bacterial colonization and biofilm formation while remaining amenable to osteoblastic cell adhesion and maturation. In an animal model, the antibiotic modified implant resists challenges by bacteria that are commonly present in periprosthetic infections. While the long-term efficacy and stability is still to be established, ongoing studies support the view that this novel type of bioactive surface has a real potential to mitigate or prevent the devastating consequences of orthopaedic infection.

10. Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues


Non-invasive treatment of injuries and disorders affecting bone and connective tissue remains a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several important roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair.


  1. Demineralized bone matrix in bone repair: History and use
  2. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration
  3. Calcium phosphate cements as drug delivery materials
  4. Silk constructs for delivery of musculoskeletal therapeutics
  5. Demineralized bone matrix as a vehicle for delivering endogenous and exogenous therapeutics in bone repair
  6. Nanofiber-based delivery of bioactive agents and stem cells to bone sites
  7. Intra-operatively customized implant coating strategies for local and controlled drug delivery to bone
  8. Immobilized antibiotics to prevent orthopaedic implant infections
  9. Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues

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Author and Curator: Ritu Saxena, Ph.D.

Role of mitochondria in cancer has long been speculated. Infact, Warburg in his 1956 publication talked about  how cancer cells exhibit a different mechanism of mitochondrial respiration than normal cells and how this basic difference in glucose metabolism could be utilized to develop targeted therapies against cancer cells. Several decades later, mitochondrial defects, both genetic and functional have been detected and associated with cancer. Here is a brief overview of the mechanisms by which mitochondrial defects could be associated with cancer:

1. Alteration in energy metabolism- well documented function of mitochondria is ATP production through oxidative phosphorylation that involved both mitochondrial and nuclear proteins. Various complexes are involved in the process of electron transport through the respiratory chain. Some electrons might leak, leading to formation of ROS. Further, certain mutations in the ETC could tamper with the mechanism of electron transfer resulting in increased leakage of electrons finally leading to an increase in ROS production. ROS has been associated with cancer, however, the exact mechanism is not known.

2. Alteration of apoptotic machinery- Mitochondrial houses several pro-apoptotic proteins including cytochrome c, apoptosis induced factor (AIF), endonuclease G, and smac/DIABLO. However, when these are released into from mitochondrial, apoptotic signaling is triggered and the cell goes through programmed death. For example, release of cytochrome c into the cytosol triggers a set of proteins referred to as caspases leading to apoptosis of the cell. The exact role of mtDNA mutations in the cellular response to anticancer agents that target apoptotic machinery has not been defined and a lot of research is being done in this area.

3. Somatic mutations- While germline mutations of the mtDNA have implicated in several diseases such as Pearson Marrow syndrome Kearns-Sayre-CPEO, Leber’s hereditary optic neuropathy, Leigh’s syndrome and several others, somatic mutations have also been a associated with several diseases, especially cancer. High rate of mutations in the mtDNA, much more than that of the nuclear genome is the result of several factors – the absence of histone proteins, close proximity to the electron transport chain, reduced repair machinery, lack of introns. The mtDNA mutations could be induced by endogenous or exogenous agents such as ROS, chemical agents, and/or radiation. The mutations could either be detrimental to its survival in which case it would vanish eventually. In case it confers growth advantage to the cell, the mutation would eventually develop into a homoplasmic state where all the alleles of the different copies of the mtDNA harbor it. It may cause a functional change of the protein derived from the mutated gene resulting in the alterations of mitochondrial function. It might be speculated that the mutated mtDNA results in increase in endogenous ROS production further leading to DNA damage, genetic instability and cancer development.


Warburg publication: http://www.ncbi.nlm.nih.gov/sites/entrez/13298683?dopt=Abstract&holding=f1000,f1000m,isrctn

Mitochondrial ROS bifurcation: http://informahealthcare.com/doi/abs/10.1080/10715760290021225

Mitochondria and apoptosis: http://www.ncbi.nlm.nih.gov/sites/entrez/11711427?dopt=Abstract&holding=f1000,f1000m,isrctn

Mitochondria and Cancer: http://www.molecular-cancer.com/content/1/1/9/#B7

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