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
Abstract
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
Abstract
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
Abstract
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
Abstract
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.
Abstract
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
Abstract
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.
Abstract
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
Abstract
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
Abstract
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
Abstract
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.
Bibliography
- Demineralized bone matrix in bone repair: History and use
- Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration
- Calcium phosphate cements as drug delivery materials
- Silk constructs for delivery of musculoskeletal therapeutics
- Demineralized bone matrix as a vehicle for delivering endogenous and exogenous therapeutics in bone repair
- Nanofiber-based delivery of bioactive agents and stem cells to bone sites
- Intra-operatively customized implant coating strategies for local and controlled drug delivery to bone
- Immobilized antibiotics to prevent orthopaedic implant infections
- Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues
Excellent review of the enormous progress and several options in the pipeline.
In a previous post I didn’t comment on the difficulties.
For many years I kept bone implantable material in the Blood Bank because the OR wouldn’t take the responsibility, and at the height of the HIV scare, we could handle it. I had to do a considerable amount of research on all sources of cadaveric bone. There was real serious risk and litigation for failure in GMP.
The maxillofacial product I have reservations about, not with respect to safety, but efficacy. The facial muscles are very different in development (membranous) and function than the long bones. The muscle around the bone is important for bone healing.
The ability to fill small breaks with a semisynthetic product is great.
The need to fill large sites with “demineralized bone” is much tougher. The GMP has to remove any risk of HIV and other possible infections.
There is a particular factor that is not brought into play here. The reference to “growth factors” sounds terrific, but I can’t fit it into the healing process.
When a fracture occurs the early phase is increased circulation to the site, and this is accompanied by bone resorption. Infection is not a problem as long as the skin is intact.
When a fracture is large, then dead bone gets walled off (cocooning) and it can’t be removed. In the early stage, osteoclasts are ignited and there is a stream of osteoclasts moving down the osteones that have to be healed and remodelled. The osteoclastic removal always precedes the osteoblastiuc refill of bone matrix. An osteoclast removes bone at a rate of 100 microns a day. The osteoblast can refill at a rate of 1 micron per day. In the long bones muscle contraction is an important influence favoring osteoblast activity.
In Paget’s disease there is a wild, uncontrolled destruction of bone. The result of the imbalance is that the bone loss is replaced by pumice bone.
Thank you Larry for sharing your personal experiences with bone tissue and for a detailed comment. I agree that it is a real challenge to find therapeutic grade bone repair materials for larger bone defects. I believe that increasing research on the effect of mechanical loads on osteogenic differentiation will add significantly in finding a therapeutic grade bone repair material. Effect of mechanics on cell differentiation has already been shown and I believe it is a matter of time that a well quantified mechanical loading regimen will add to the repertoire of making osteocytes from stem cells, although it is quite challenging.
Indeed osteoclasts lead the way in forming the resorptive tunnel, which is then filled by osteoblasts that differentiate into osteocytes after/along with mineralisation. Osteocytes, however, orchestrate the process of bone remodelling by communicating with the osteoclasts and/or osteoblasts after sensing the external mechanical loads. As you mentioned, it is the derangement of this fine balance of bone resorption and bone formation that leads to disease states such Paget’s, osteoporosis, osteopetrosis…just to name a few.
I did not read it yet. Looks phenomenal.
Dr. Larry, thank you for your comment, the recollection from your days at the Blood Bank are very significant for the young scientist reading the comment.
Then the process explanation of ORFS.
[…] Link: Targeted delivery of therapeutics to bone and connective tissues … […]
A viral,
Thank you for issuing a series of posts on this very inportant topic from the perspective you have chosen: therapeutic modalities in bone repair.
I shadowed in 2007 one hundred hours at BWH in Boston, interventional radiology diagnostic center, CVIDC, where cases on mascular skeletal bone repair took place with cement injection, type three, above were performed routinely, some required extensive geometrical measurements and collaboration with efforts from Mascular Skeletal orthopedics department during the intervention performed by an interventional radiologist with extertise in vertebral modification by cement injection.
I assume that in your forthcoming posts you will continue to write on Nitric Oxide and Bone repair. In addition to being NOVICE, in practice in very few places around the Globe, it’s physiology has I believe the greatest potential for
Therapeutics of the connective tissue attached to the bone. All methods above have focused on bone repair rather than on the connective tissue repair, for which NO will prove to be both essential therapy and among the cardinal in efficacy as it will be further developed, perfected and widely deployed.
Orthopedics is a field with old entrenched technologies and great eagerness for innovations and fast adoption of new modalities of treatment of bone disease.
In 1993, I met Dr. Forrester, Chief of Orthopedics surgery at Newton-Wellesley Hospital in Newton, MA, he was few months before his retirement at age +80, he said, “in orthopedics, the patient always get better, this is not the case in Cardiology or Oncology, how happy I am to have chosen Orthpedics early on”
You are to edifying us all about the new potential on Nitric Oxide in the therapy of connective tissue in the context of Bone disease, marvelous a way to march on and a research direction to aim to!
Thank you for your detailed response. I will indeed focus on NO physiology and its role predominantly in bone and cartilage. These two topics remain my principle areas of interest. I really enjoyed the above post as it brings to light the driving force for basic research towards application in bone field. I am excited that our other colleagues (EAWs) will keep up the work on NO in their respective fields.
Interesting series of papers. Would like to know more. Please give the author and complete citation for each article in the bibliography.
Thank you and indeed I found it quite interesting series too. I have added the links to each paper in their titles and the bibliography, but I will give more informative bibliography soon. I ll update this one too along with my next post on this. Thank you once again
Aviral,
I myself embarked on the Nitric Oxide journey and made it a Thrust for the venture because it is so important, thus, mobilized EVERY EAW to write in their area.
You are our Research Category Owner and as such, you have create the spread seet and will maintain a log of all posts on NO for referencing and Pinkbacks and monitor that the pardigm is filing up.
I am contemplating to make NO and Mitochondria two pages, like Home, About, Contributors’ Biographies, NO Research, Mito Research. Then Under NO Research Page, all the posts, you click on one and get there. May be not sure, what do you say??
It is indeed a good idea to have a separate tab for these topics, but I was also thinking that when one clicks on the category of NO in health and disease (or other categories), thats what one gets… a dedicated page with all the posts on this topic. A separate tab/page will surely increase its presence on the website and highlight the importance of these basic and widespread topics.
When I spent two years in the Navy with Lent C Johnson in the Orthopedic Branch, the Orthopedic Surgeons told me “an orthopod looks like a guerilla, walks like a guerrilla, but is 100 times smarter”.
I have several sets of lectures on: bone growth and development, fracture and fracture healing, septic bone and septic joint, metabolic bone disease, genetic disorders (probably from McKusick’s work), benign bone lesions, and malignant tumors. (I have another several hundred slides). I haven’t figured out what to do with them but I spent several days reviewing it all about 2 years ago.
Ted Kennedy tried to save the AFIP and Tumor registry before his death, to no avail. This was a historical treasure. There were cases that went back to the Civil War. What civilized country is so careless.
John Hunter, the father of modern surgery practiced in the seven years war of GB and France. He realized that he had to pull the soldiers out of the mud before doing anything more. He paid “graverobbers”, a feat that wasn’t repeated until PT Barnum was mayor of Bridgeport. That’s another story. Unfortunately, he went bankrupt and lost the famous Museum. The greatest feat was when the pituitary giant paid to have his body dumped at sea to avoid JH, but JH paid more to have the body brought back for the Museum that I think is in Edinborough.
Dr. Larry,
Your life stories covers few areas in Medicine. Here you are telling the Orthopedics angle.
[…] This post is in the second part of the reviews that focuses on the current status of drug delivery to bone and the issues facing this field. The first part can be accessed here […]
[…] http://pharmaceuticalintelligence.com/2012/09/23/targeted-delivery-of-therapeutics-to-bone-and-conne… […]
[…] http://pharmaceuticalintelligence.com/2012/09/23/targeted-delivery-of-therapeutics-to-bone-and-conne… […]
[…] http://pharmaceuticalintelligence.com/2012/09/23/targeted-delivery-of-therapeutics-to-bone-and-conne… […]
[…] http://pharmaceuticalintelligence.com/2012/09/23/targeted-delivery-of-therapeutics-to-bone-and-conne… […]
[…] http://pharmaceuticalintelligence.com/2012/09/23/targeted-delivery-of-therapeutics-to-bone-and-conne… […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette