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Drug delivery to bony tissue
Advanced Drug Delivery Reviews 94 (2015) 1–2
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
Preface
Drug delivery to bony tissue
Bone is one of the few organs in the body that can spontaneously heal and restore function without scarring. However, the natural repair of bone tissue is not always satisfactory. Trauma and cancer patients often present large bone defects that are not able to heal without further medical intervention. Additionally, co-morbidities like osteoporosis and diabetes highly impact bone quality, making the bone healing process a challenging one. There is a clear unmet clinical need for bone regeneration and repair. Current treatment options for bone non-union fractures and/or large bone defects are expensive and not always effective. Autologous bone can be harvested, mostly from the iliac crest, and can be subsequently used as bone filling material. It present osteoconductive and osteoinductive properties, and is considered as the gold standard treatment for bone healing clinically. Unfortunately, they are clear limitations. The availability of host donor material is limited and the quality of the harvested bone is not always optimal (especially when comorbidities are present). Issues like fractures and pain at the harvesting side together with a high risk of infections have been also reported. During the last decades, the field of tissue engineering has focused on the development of approaches for the regeneration of many tissues and organs. Mainly based on the combination of biomaterials, growth factors and cells, fair progress has been made in the regenerative medicine field. Bone tissue has not been an exception. In fact, bone is maybe one of the tissues more explored by tissue engineers attempting its regeneration. Many materials of diverse origin have been developed and are currently clinically used as bone fillers. These mainly-synthetic materials possess good osteoconductive properties and are mostly designed to mimic the composition of the natural bone. However, they often lack osteoinductive properties. These osteoinductive features can be achieved by using growth factors that are known to be crucially involved in the regulation of new bone formation during development. Examples are bone morphogenetic properties (BMPs) and vascular endothelial growth factor (VEGF). Since their discovery in 1965, BMPs have been one of the most studied growth factors related to bone induction. As a result, BMP-2 and BMP-7 (although this one is not on the market anymore) are approved for clinical use. BMP-7 has been used and BMP-2 is often used in treatments of patients with compromised bone healing, critical defects, and spinal fusions among others. They have clear osteoinductive properties. However, supraphysiological concentrations of those growth factors are administered. This is associated with heterotopic bone formation and high costs. In addition, vascularization of the newly formed bone is often absent or insufficient. These limitations have inspired researchers to constantly explore new approaches to improve local growth factor delivery to bone tissue. Here, a combination of biomaterials and growth factors could be highly
http://dx.doi.org/10.1016/j.addr.2015.10.018 0169-409X/© 2015 Published by Elsevier B.V.
advantageous. An osteoconductive material can be used as drug delivery matrix that may protect BMPs from degradation and at the same time locally deliver this growth factor in a controlled manner. Following this approach, osteoconductive and osteoinductive properties as well as adequate mechanical properties of the filling material can be achieved. Other scientists have investigated the use of different osteoinductive molecules to overcome limitations associated to growth factors. Small molecules and peptides feature osteoinductive properties and are highly stabile and less immunogenic when compared to growth factors. Moreover, some of these molecules may present a multi-inductive capacity such as simultaneous osteo- and angiogenesis. They are being investigated to improve the vascularization of the newly formed bone during the healing process. With the same purpose of vascularization, many cellular approaches have been claimed to be advantageous as well. There are many approaches that are being currently investigated aiming to improve bone healing. However, new and save technologies are still needed to address limitations associated with the use of autografts and high dosage of growth factors. In this theme issue, we attempt to summarize recent development on biomaterials, cellular approaches and drug delivery systems for bone healing and their translation to the clinical arena. Contributions of distinguished scientists in the field of bone tissue engineering are grouped together here with the aim to present an outstanding up-todate issue to the reader. The issue starts with a review by Kurt Hankenson and colleagues (http://dx.doi.org/10.1016/j.addr.2015.09.008) on signaling factors associated with the various stages of fracture healing. The authors also emphasize the potential use of these factors as targets to promote bone regeneration. Balmayor (http://dx.doi.org/10.1016/j.addr.2015. 04.022) provides a comprehensive review of small osteoinductive molecules stressing their advantages over growth factors for regenerative medicine. Some molecules that possess simultaneous osteo- and angiogenic inductive capacities are presented as well. The Tabata laboratory (http://dx.doi.org/10.1016/j.addr.2015.06.003) then discusses the recent advances on drug delivery systems for BMPs and other growth factors for bone engineering. They also emphasize systems that are able to release two or more bioactive factors at the same time or following a coordinated path. Both, Balmayor and Tabata present the challenges on the clinical translation of these types of molecules. Hubbell and his group (http://dx.doi.org/10.1016/j.addr.2015.04.007) present an outstanding summary of the most extensively explored growth factors to enhance bone regeneration (i.e. BMPs, VEGF-A, PDGF-BB and FGF-2). The authors clearly state the limitations that jeopardize the clinical translation of these factors, and present their approach to overcome
2
Preface
these drawbacks. This approach, based on the engineering of growth factor molecules to interact with or bind to biomaterials matrices may provide retention of these factors within matrices considerably accentuating the growth factor functions. Moving to a more material perspective, Agarwal and García (http:// dx.doi.org/10.1016/j.addr.2015.03.013) take the reader on a wonderful journey through the different strategies for engineering implants in order to enhance their osteointegration with the host tissue as well as cell adhesion and growth factors release. Highlights are surface modifications like functionalization and coatings or engaging integrin molecules via RGD, collagen and fibronectin sequences adsorbed or conjugated on implant surfaces. Azevedo and Pashkuleva (http://dx. doi.org/10.1016/j.addr.2015.08.003) focus on peptides and polysaccharides as biomaterials for growth factor release. Peptides have the property of self-assembly to form nanocarriers that can be at the same time functionalized to provide control retention of growth factors. On the other hand, these nanocarriers can also be obtained by using polysaccharides through polyelectrolyte complexation. The authors present an outstanding review on the current progress of these two types of materials and the future perspectives in the field of drug delivery to bone tissue. Similarly, Jayaraman and colleagues (http://dx.doi.org/10.1016/ j.addr.2015.09.007) also highlight the advantages of nano-sized carriers for drug delivery applications. The authors dedicated their review to electrospray nanoparticles for the controlled release of growth factors, antibiotics, proteins and genes. An in-depth review on the fabrication of these nanoparticles using natural, synthetic polymers and their copolymers, inorganic and metallic materials as well as biomolecules is presented. The Ducheyne research group (http://dx.doi.org/10.1016/j. addr.2015.05.015) closes the biomaterials part of our issue with a remarkable review on silicon oxide based materials. The authors not only provide a summary on the scientific background on these materials, but also present several examples of their current clinical applications in the field of bone engineering. As stated above, vascularization is of utmost importance for bone healing. Therefore, our theme issue includes a review from Prof. Kirkpatrick's group (http://dx.doi.org/10.1016/j.addr.2015.03.012) on pro-angiogenic factors released by co-culture systems as key factor to improve vascularization during bone repair. In the review, the authors stress the major importance of vascularization for bone healing and how co-culture systems of human cells such as endothelial cells and MSCs or osteoblasts trigger this phenomenon. The authors not only present these co-culture systems in 2D, but also in 3D culture models in which biomaterials and growth factors can be present. Regarding a more challenging regeneration scenario, the van Griensven's group (http://dx.doi.org/10.1016/j.addr.2015.03.004) provides the reader with a comprehensive review on the regeneration of the enthesis (i.e. interface tendon/ligament-to-bone). These native interfaces are highly complex tissues, that once injured do not spontaneously heal. They are essential to ensure musculoskeletal motion, and tissue engineers are constantly striving towards the development of
approaches that ultimately lead to the regeneration of these interfaces. van Griensven and colleagues focuses on tissue engineering approaches for enthesis engineering depicting biomaterials, cells and growth factors systems while highlighting their benefits and drawbacks. The authors also provide their point of view related to future challenges that the tissue engineering field faces in the development of a functional enthesis substitute. One of the main aims of tissue engineering scientists after developing new therapeutic products is their satisfactory transfer to the clinics. To ensure a satisfactory clinical translation, animal studies are required. The suitable animal model for the different injuries or pathologies is, however, still a matter of much debate. Surprisingly, a growing number of tissue engineering preclinical studies lack of reproducibility even when the same animal model is selected. As a result, the rapid transfer to the clinics of the tested tissue engineering products is highly compromised. To this end, the theme issue concludes with the reviews by Mark Chong Seow Khoon (http://dx.doi.org/10.1016/j.addr.2014.12.007) and Martijn van Griensven (http://dx.doi.org/10.1016/j.addr.2015.07.006), which deal with in vivo models for preclinical studies. The first review focuses on in vivo models to investigate bone metastasis with great detail on “humanized” mice models and their advantages. The second one thoroughly describes animal models that have been specifically designed for testing drug delivery matrices to the musculoskeletal system. In this review, the author provides the reader with a set of questions that may support the selection of the most adequate animal model, e.g. which is the main research question; is a functional or mechanistic evaluation needed? Which is the type of bone defect investigated: loadbearing or non-load-bearing? Furthermore, the ARRIVE guidelines for accurately reporting preclinical studies are presented and discussed. Much has been achieved in the field of bone tissue engineering and more specifically in the development of drug delivery systems targeting bone tissue. Some of the main progresses in the field are described here in this theme issue. However, we still face clear challenges in the regeneration of a fully functional and vascularized bone tissue or even in the engineering of more complex systems like the hard-to-soft tissue interface, e.g. tendon/ligament-to-bone. In this issue, each author has clearly presented the limitations that the field face and the possible approaches to overcome these drawbacks each from a very different perspective, i.e. molecules and growth factors, biomaterials and cellular solutions were discussed here. Hence, we anticipate that this special issue provides important insight on the clinical translation of bone tissue engineering products. We as invited editors are pleased to present this issue to the readers of Advanced Drug Delivery Reviews, which condenses the work of some of the most prestigious scientists in the bone engineering field. Elizabeth R. Balmayor Martijn van Griensven
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
Preface
Drug delivery to bony tissue
Bone is one of the few organs in the body that can spontaneously heal and restore function without scarring. However, the natural repair of bone tissue is not always satisfactory. Trauma and cancer patients often present large bone defects that are not able to heal without further medical intervention. Additionally, co-morbidities like osteoporosis and diabetes highly impact bone quality, making the bone healing process a challenging one. There is a clear unmet clinical need for bone regeneration and repair. Current treatment options for bone non-union fractures and/or large bone defects are expensive and not always effective. Autologous bone can be harvested, mostly from the iliac crest, and can be subsequently used as bone filling material. It present osteoconductive and osteoinductive properties, and is considered as the gold standard treatment for bone healing clinically. Unfortunately, they are clear limitations. The availability of host donor material is limited and the quality of the harvested bone is not always optimal (especially when comorbidities are present). Issues like fractures and pain at the harvesting side together with a high risk of infections have been also reported. During the last decades, the field of tissue engineering has focused on the development of approaches for the regeneration of many tissues and organs. Mainly based on the combination of biomaterials, growth factors and cells, fair progress has been made in the regenerative medicine field. Bone tissue has not been an exception. In fact, bone is maybe one of the tissues more explored by tissue engineers attempting its regeneration. Many materials of diverse origin have been developed and are currently clinically used as bone fillers. These mainly-synthetic materials possess good osteoconductive properties and are mostly designed to mimic the composition of the natural bone. However, they often lack osteoinductive properties. These osteoinductive features can be achieved by using growth factors that are known to be crucially involved in the regulation of new bone formation during development. Examples are bone morphogenetic properties (BMPs) and vascular endothelial growth factor (VEGF). Since their discovery in 1965, BMPs have been one of the most studied growth factors related to bone induction. As a result, BMP-2 and BMP-7 (although this one is not on the market anymore) are approved for clinical use. BMP-7 has been used and BMP-2 is often used in treatments of patients with compromised bone healing, critical defects, and spinal fusions among others. They have clear osteoinductive properties. However, supraphysiological concentrations of those growth factors are administered. This is associated with heterotopic bone formation and high costs. In addition, vascularization of the newly formed bone is often absent or insufficient. These limitations have inspired researchers to constantly explore new approaches to improve local growth factor delivery to bone tissue. Here, a combination of biomaterials and growth factors could be highly
http://dx.doi.org/10.1016/j.addr.2015.10.018 0169-409X/© 2015 Published by Elsevier B.V.
advantageous. An osteoconductive material can be used as drug delivery matrix that may protect BMPs from degradation and at the same time locally deliver this growth factor in a controlled manner. Following this approach, osteoconductive and osteoinductive properties as well as adequate mechanical properties of the filling material can be achieved. Other scientists have investigated the use of different osteoinductive molecules to overcome limitations associated to growth factors. Small molecules and peptides feature osteoinductive properties and are highly stabile and less immunogenic when compared to growth factors. Moreover, some of these molecules may present a multi-inductive capacity such as simultaneous osteo- and angiogenesis. They are being investigated to improve the vascularization of the newly formed bone during the healing process. With the same purpose of vascularization, many cellular approaches have been claimed to be advantageous as well. There are many approaches that are being currently investigated aiming to improve bone healing. However, new and save technologies are still needed to address limitations associated with the use of autografts and high dosage of growth factors. In this theme issue, we attempt to summarize recent development on biomaterials, cellular approaches and drug delivery systems for bone healing and their translation to the clinical arena. Contributions of distinguished scientists in the field of bone tissue engineering are grouped together here with the aim to present an outstanding up-todate issue to the reader. The issue starts with a review by Kurt Hankenson and colleagues (http://dx.doi.org/10.1016/j.addr.2015.09.008) on signaling factors associated with the various stages of fracture healing. The authors also emphasize the potential use of these factors as targets to promote bone regeneration. Balmayor (http://dx.doi.org/10.1016/j.addr.2015. 04.022) provides a comprehensive review of small osteoinductive molecules stressing their advantages over growth factors for regenerative medicine. Some molecules that possess simultaneous osteo- and angiogenic inductive capacities are presented as well. The Tabata laboratory (http://dx.doi.org/10.1016/j.addr.2015.06.003) then discusses the recent advances on drug delivery systems for BMPs and other growth factors for bone engineering. They also emphasize systems that are able to release two or more bioactive factors at the same time or following a coordinated path. Both, Balmayor and Tabata present the challenges on the clinical translation of these types of molecules. Hubbell and his group (http://dx.doi.org/10.1016/j.addr.2015.04.007) present an outstanding summary of the most extensively explored growth factors to enhance bone regeneration (i.e. BMPs, VEGF-A, PDGF-BB and FGF-2). The authors clearly state the limitations that jeopardize the clinical translation of these factors, and present their approach to overcome
2
Preface
these drawbacks. This approach, based on the engineering of growth factor molecules to interact with or bind to biomaterials matrices may provide retention of these factors within matrices considerably accentuating the growth factor functions. Moving to a more material perspective, Agarwal and García (http:// dx.doi.org/10.1016/j.addr.2015.03.013) take the reader on a wonderful journey through the different strategies for engineering implants in order to enhance their osteointegration with the host tissue as well as cell adhesion and growth factors release. Highlights are surface modifications like functionalization and coatings or engaging integrin molecules via RGD, collagen and fibronectin sequences adsorbed or conjugated on implant surfaces. Azevedo and Pashkuleva (http://dx. doi.org/10.1016/j.addr.2015.08.003) focus on peptides and polysaccharides as biomaterials for growth factor release. Peptides have the property of self-assembly to form nanocarriers that can be at the same time functionalized to provide control retention of growth factors. On the other hand, these nanocarriers can also be obtained by using polysaccharides through polyelectrolyte complexation. The authors present an outstanding review on the current progress of these two types of materials and the future perspectives in the field of drug delivery to bone tissue. Similarly, Jayaraman and colleagues (http://dx.doi.org/10.1016/ j.addr.2015.09.007) also highlight the advantages of nano-sized carriers for drug delivery applications. The authors dedicated their review to electrospray nanoparticles for the controlled release of growth factors, antibiotics, proteins and genes. An in-depth review on the fabrication of these nanoparticles using natural, synthetic polymers and their copolymers, inorganic and metallic materials as well as biomolecules is presented. The Ducheyne research group (http://dx.doi.org/10.1016/j. addr.2015.05.015) closes the biomaterials part of our issue with a remarkable review on silicon oxide based materials. The authors not only provide a summary on the scientific background on these materials, but also present several examples of their current clinical applications in the field of bone engineering. As stated above, vascularization is of utmost importance for bone healing. Therefore, our theme issue includes a review from Prof. Kirkpatrick's group (http://dx.doi.org/10.1016/j.addr.2015.03.012) on pro-angiogenic factors released by co-culture systems as key factor to improve vascularization during bone repair. In the review, the authors stress the major importance of vascularization for bone healing and how co-culture systems of human cells such as endothelial cells and MSCs or osteoblasts trigger this phenomenon. The authors not only present these co-culture systems in 2D, but also in 3D culture models in which biomaterials and growth factors can be present. Regarding a more challenging regeneration scenario, the van Griensven's group (http://dx.doi.org/10.1016/j.addr.2015.03.004) provides the reader with a comprehensive review on the regeneration of the enthesis (i.e. interface tendon/ligament-to-bone). These native interfaces are highly complex tissues, that once injured do not spontaneously heal. They are essential to ensure musculoskeletal motion, and tissue engineers are constantly striving towards the development of
approaches that ultimately lead to the regeneration of these interfaces. van Griensven and colleagues focuses on tissue engineering approaches for enthesis engineering depicting biomaterials, cells and growth factors systems while highlighting their benefits and drawbacks. The authors also provide their point of view related to future challenges that the tissue engineering field faces in the development of a functional enthesis substitute. One of the main aims of tissue engineering scientists after developing new therapeutic products is their satisfactory transfer to the clinics. To ensure a satisfactory clinical translation, animal studies are required. The suitable animal model for the different injuries or pathologies is, however, still a matter of much debate. Surprisingly, a growing number of tissue engineering preclinical studies lack of reproducibility even when the same animal model is selected. As a result, the rapid transfer to the clinics of the tested tissue engineering products is highly compromised. To this end, the theme issue concludes with the reviews by Mark Chong Seow Khoon (http://dx.doi.org/10.1016/j.addr.2014.12.007) and Martijn van Griensven (http://dx.doi.org/10.1016/j.addr.2015.07.006), which deal with in vivo models for preclinical studies. The first review focuses on in vivo models to investigate bone metastasis with great detail on “humanized” mice models and their advantages. The second one thoroughly describes animal models that have been specifically designed for testing drug delivery matrices to the musculoskeletal system. In this review, the author provides the reader with a set of questions that may support the selection of the most adequate animal model, e.g. which is the main research question; is a functional or mechanistic evaluation needed? Which is the type of bone defect investigated: loadbearing or non-load-bearing? Furthermore, the ARRIVE guidelines for accurately reporting preclinical studies are presented and discussed. Much has been achieved in the field of bone tissue engineering and more specifically in the development of drug delivery systems targeting bone tissue. Some of the main progresses in the field are described here in this theme issue. However, we still face clear challenges in the regeneration of a fully functional and vascularized bone tissue or even in the engineering of more complex systems like the hard-to-soft tissue interface, e.g. tendon/ligament-to-bone. In this issue, each author has clearly presented the limitations that the field face and the possible approaches to overcome these drawbacks each from a very different perspective, i.e. molecules and growth factors, biomaterials and cellular solutions were discussed here. Hence, we anticipate that this special issue provides important insight on the clinical translation of bone tissue engineering products. We as invited editors are pleased to present this issue to the readers of Advanced Drug Delivery Reviews, which condenses the work of some of the most prestigious scientists in the bone engineering field. Elizabeth R. Balmayor Martijn van Griensven