Review

Subject Category: Stem cells and regenerative medicine

Citation: Experimental & Molecular Medicine (2013) 45, e57; doi:10.1038/emm.2013.118
Published online 15 November 2013

In situ tissue regeneration through host stem cell recruitment
Open

In Kap Ko1, Sang Jin Lee1, Anthony Atala1 and James J Yoo1

1Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA

Correspondence: Professor JJ Yoo, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. E-mail: jyoo@wakehealth.edu

Received 23 July 2013; Revised 31 July 2013; Accepted 6 August 2013

Top

Abstract

The field of tissue engineering has made steady progress in translating various tissue applications. Although the classical tissue engineering strategy, which involves the use of culture-expanded cells and scaffolds to produce a tissue construct for implantation, has been validated, this approach involves extensive cell expansion steps, requiring a lot of time and laborious effort before implantation. To bypass this ex vivo process, a new approach has been introduced. In situ tissue regeneration utilizes the body’s own regenerating capacity by mobilizing host endogenous stem cells or tissue-specific progenitor cells to the site of injury. This approach relies on development of a target-specific biomaterial scaffolding system that can effectively control the host microenvironment and mobilize host stem/progenitor cells to target tissues. An appropriate microenvironment provided by implanted scaffolds would facilitate recruitment of host cells that can be guided to regenerating structural and functional tissues.

Keywords:

bioactive molecules; biomaterials; in situ tissue regeneration; protein delivery system; stem cells; tissue engineering

Top

Introduction

Surgical reconstructive procedures often require the use of additional tissues, such as autograft, allograft or xenograft, in order to restore normal anatomical and functional tissue configurations. However, these materials are often associated with complications such as donor site morbidity, limited availability and host tissue reactivity.1, 2 Cell-based tissue engineering has emerged as a promising approach to overcome these limitations, as this technology enables the fabrication of functional tissues or organs that could be used for reparative procedures in patients.3 The basic approach is to create bioengineered tissues or organs by combining patient’s own cells with a natural and/or synthetic biomaterial scaffold under suitable culture conditions, resulting in tissue constructs that can be implanted in vivo. However, this approach requires a donor tissue biopsy and extensive cell expansion steps before implantation for therapy. Moreover, isolated tissue-derived primary cells are often heterogeneous and difficult to standardize. Thus, obtaining a reliable and reproducible cell source has been one of the challenging elements of cell-based approaches. This has motivated the development of a new strategy that eliminates the ex vivo cell manipulation before implantation, and this approach would decrease the time, effort and resources required to generate a tissue/organ substitute.

Recent progress in tissue engineering and regenerative medicine has adopted the concept of utilizing endogenous cells for in situ tissue regeneration. The principle of in situ tissue regeneration is to utilize the body’s own biologic resources and its reparative capability by using a target-specific biomaterial system to recruit host stem or tissue-specific progenitor cells to the site of injury. This novel approach would allow for a damaged tissue to be regenerated without the need for cell transplantation (Figure 1). When scaffolds incorporated with bioactive molecules are implanted in vivo, sustained release of the bioactive cues unlocks the body’s own regenerative capability. In turn, this induces the mobilization of tissue-specific host stem/progenitor cells, drives proliferation and differentiation of these recruited cells into the targeted cell types and regenerates functional tissues. This review discusses the recent development of approaches for in situ tissue regeneration, particularly focusing on the strategies that enhance host stem or progenitor cells into the target-specific scaffolds, and present some of the applications of in situ tissue regeneration.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

A strategy for in situ tissue regeneration.

Full figure and legend (81K)

Top

Basic considerations for in situ tissue regeneration

The success of in situ tissue regeneration relies on effective recruitment of host stem or progenitor cells into the implanted biomaterial scaffolds and induction of the infiltrating cells into tissue-specific cell lineages for functional tissue regeneration. To achieve this, a target-specific scaffolding system, serving as a template, needs to be designed in order to enable (‘instructs’) the fate of the recruited host cells to proliferate and differentiate into a desired tissue type.4 Sustained delivery of biological cues, such as bioactive molecules, from the implanted scaffold could play an important role in guiding host cells to form a well-integrated functional structure.5 Moreover, a well-designed combination of biological cues with biomaterial scaffolds would provide appropriate microenvironments for efficient cellular specification within the implanted scaffold.

Host cell sources for in situ tissue regeneration

It has been demonstrated that adult stem cells that contain self-renewal and differentiation capability can be isolated from various tissues and organs, including brain, liver, circulating blood, heart, skin, kidney, muscle and fat.6, 7, 8, 9, 10, 11, 12 Most adult stem cells are quiescent and reside in a specialized microenvironment, which is called a ‘stem cell niche’. In response to regulatory signals that originate from tissue injury, these stem cells become activated and begin repairing process. In addition to tissue-specific adult stem cells that are primarily responsible for tissue regeneration processes, bone marrow-derived stem cells have been identified as important cell sources that contribute their regenerating capacity to other tissues. The bone marrow harbors multiple distinct stem/progenitor cells that include hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs). HSCs are responsible for the production of all circulating blood cells such as myeloid, erthyroid and lymphoid lineages. An important role of the HSC population for tissue regeneration is to provide paracrine bioactive factors to regenerative cells and occasionally transdifferentiate into desired tissue-specific lineages.13 Another cell population contained in the bone marrow is stromal cells or MSCs that exhibit multipotent capabilities to differentiate into a variety of cell types in vitro and in vivo.

Interestingly, many reports have shown that MSC populations that express similar set of cell surface antigens can be isolated from bone, cartilage, muscle, bone marrow stroma, tendon, fat and other connective tissues,14 and these MSC populations have been widely used in preclinical and clinical applications for tissue regeneration. These cells are known to modulate the immune system and/or provide trophic factors necessary for tissue-specific regeneration.15 However, the specific identity of these MSC populations is still unclear and further studies are required for understanding the origin and contributions of these cells to tissue regeneration. EPCs6 are another important cell source that are actively involved in promoting angiogenesis at the injury site. Facilitating neovascularization through EPCs is particularly beneficial in tissue regeneration and ischemic tissue injury.

Macrophages that play an important role in inflammatory response and foreign body reaction are found at the injury site during the tissue repair and remodeling process.16 Recent reports have shown that macrophages are an important determinant during tissue remodeling in the context of regenerative medicine.17 The proinflammatory macrophages, designated as an M1 phenotype, are involved in chronic inflammation and foreign body reactions,18 whereas M2 macrophage phenotypes are associated with anti-inflammation, immunomodulation and tissue remodeling processes. A better understanding of the mechanisms underlying differential infiltration of the macrophage populations into scaffolds will aid in controlling the specific type of macrophage recruitment and may result in beneficial effects on the desired tissue regeneration.17

Although certain types of host cells have been identified in inflammatory responses and foreign body reactions, cell populations that infiltrate into biomaterial scaffolds are poorly understood. It is important to investigate the possibilities to use the body’s biologic and environmental resources for tissue regeneration in situ. Recruitment of host cells into an implanted scaffold as part of tissue repairing process has been examined. In our previous study,19 poly(glycolic acid) nonwoven scaffold was used to address this dogma. This biomaterial implant was designed to enhance diffusion and accommodate host cell infiltrates into the highly porous structures. The results of this study showed that the number of host cells infiltrating into the implant increased for up to 3 weeks after implantation and began to decrease thereafter, as collagen accumulated to fill the pores of implanted scaffold. Interestingly, we observed that a small proportion of infiltrated host cells within the implants had multilineage potential (Figure 2). These results indicate that some of the host stem cells that mobilized into the biomaterial were multipotent, and given an appropriate microenvironment, they differentiated into tissue-specific cell lineages at the implant site.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Multidifferentiation capability in vitro of the infiltrated cells into the biomaterial scaffold: (a) Sca-1+ population of the cell infiltrate, (b) osteogenic, (c) myogenic, (d) adipogenic and (e) endothelial differentiation under appropriated culture conditions.19 α-SMA, α-smooth muscle actin; PECAM-1, platelet/endothelial cell adhesion molecule; Sca-1, stem cell antigen-1; vWF, von Willebrand factor.

Full figure and legend (148K)

Biomaterial scaffolds for in situ tissue regeneration

Creation of bioengineered tissue requires a scaffold, which provides structural support until the mobilized cells form functional tissue in vivo. Although the properties of scaffolds may vary depending on the targeting tissues, the general requirements of a scaffolding system are biological stability, biodegradability and temporal structural integrity. The scaffold’s internal architecture should provide adequate permeability for establishing functional vascularization following implantation. The latter is critically important as this porous structure can not only facilitate space for the recruited cells to reside, but also permit incorporation of bioactive molecules and biophysical cues that enhance cell migration, proliferation and differentiation to produce a biofunctional host stem cell niche.20 To design a tissue-specific scaffolding system for in situ tissue regeneration, the scaffolds should possess the ability to (1) regulate inflammation for minimized fibrotic formation, (2) utilize host microenvironment for recruiting host stem/progenitor cells and (3) control tissue-specific cell differentiation within the scaffold.

Biomaterials used for scaffolding can be naturally derived or synthetic polymers. Natural materials include polysaccharides and proteins. Polysaccharides that have been widely used for this purpose include cellulose, alginate, hyaluronic acid, starch, dextran, heparin, chitin and chitosan.21 Proteins are the primary components of tissues or organs and have been used for various biomedical applications. Collagen, which is the most abundant protein in mammals, has been used as scaffold materials because of the ease of processing as well as its ability to induce minimal inflammatory and immune responses. Collagen has been approved by the US Food and Drug Administration (FDA) for many types of biomedical applications, including wound dressings and artificial skin.22 Collagen can be configured into various structures such as films, fibers and sponges.23, 24, 25 Decellularized collagen-rich tissue scaffolds have received much attention recently because of their ability to maintain microtissue architecture.26, 27 In addition, these acellular tissue matrices have been shown to support cell ingrowth and tissue regeneration.28

Synthetic polymeric biomaterials such as biodegradable polyesters, including poly(glycolic acid), poly(lactic acid) and poly(lactide-co-glycolide) (PLGA), are widely used in tissue engineering and regenerative medicine. The use of these polymers was approved by the FDA for human use in a variety of applications, including surgical sutures.29 These biodegradable polymers are nontoxic during the degradation process in vivo, and are eventually removed from the body in the form of carbon dioxide and water.29 These polymers possess thermoplastic properties and can be easily fabricated into various configurations with controlled microstructure and porosity using a number of processing techniques, including molding, extrusion,30 solvent casting,31 phase separation techniques and gas foaming techniques.32, 33 More recently, electrospinning techniques have been developed to quickly create highly porous scaffolds in various conformations, including nanostructures.32, 34, 35, 36 Other biodegradable synthetic polymers used for tissue regeneration applications include poly(anhydrides) and poly(ortho-esters).37

Biochemical signaling for in situ tissue regeneration

A key to in situ tissue regeneration in the initial stage is proficient recruitment of host stem or progenitor cells into an implanted scaffold. However, adult stem cell populations in the body are generally too low in number to have a significant impact on acceleated tissue regeneration. In most cases of tissue regeneration, bone marrow-derived stem cells have contributed to regeneration, and therefore it is worthwhile to target these cells to be effectively mobilized into the peripheral blood system. During this mobilization, homing and engraftment process, other cytokines and chemoattractants are able to increase the efficacy of migration to the injury site. Table 1 shows several bioactive molecules used for in situ tissue regeneration.


Substance P (SP) is a neuropeptide that functions as a neurotransmitter and neuromodulator. A recent report showed strong evidence that released SP after corneal injury was able to mobilize a high number of stromal-like CD29+ cells (MSC-like cells) from bone marrow into peripheral blood and drive migration and participation in the repair processes of the cornea injury.38 This study shows that under the optimal culture conditions in vitro, the SP-induced CD29+ MSC-like cells are able to demonstrate multidifferentiation capability by forming bone, cartilage and fat cells. These results indicate that SP is expected to play a positive role in tissue repair39 based on the multipotency features. In terms of therapeutic aspects, the use of SP appears to be a cost-effective treatment because of high efficacy of host MSC-like cell mobilization with a single injection. A recent report also stressed positive roles of SP in reparative neovascularization.40 In this report, patients with myocardial infarction showed high concentration of SP in the blood, which increased host progenitor cell mobilization, whereas suppression of SP levels resulted in a decreased number of host therapeutic progenitor cells. The study team concluded that SP-based nociceptive signaling may represent a possible target of regenerative medicine. Therefore, the use of stem cell-stimulating factors such as SP is a possible approach to accelerate the neovascularization process.

It is well known that retention of stem or progenitor cells in the bone marrow is through the interaction between the C-X-C chemokine receptor 4 (CXCR4) on the surface of stem/progenitor cells and stromal cell-derived factor-1α (SDF-1α) on the surface of bone marrow stromal cells.41 When the retention axis is disrupted, the progenitor cells are released from the bone marrow stroma and mobilized into the peripheral blood. One of the mobilization-accelerating factors is granulocyte-colony-stimulating factor (G-CSF) and it has been widely used for clinical trials.42 It was reported that CD34+ HSCs can be effectively mobilized into the peripheral blood from the bone marrow through disruption of the SDF-1/CXCR4 axis.41 In an approach for in situ tissue regeneration, several reports showed that G-CSF has been used as a single injection or directly incorporated into the implanted scaffold. A single injection of G-CSF for tissue regeneration has been conducted to accelerate EPC recruitment on implanted small-diameter vascular constructs.43 It was shown that administration of G-CSF induced significant recruitment of CD34+, CD133+ EPCs into the vascular graft, generated endothelium and inhibited neointimal hyperplasia of a small-diameter heparinized decellularized vascular graft. A recent approach showed the efficiency of released G-CSF from a hydrogel scaffold for enhancing EPC mobilization.44 This group developed a hydrogel system incorporating G-CSF and showed that intramuscularly injected hydrogel significantly enhanced mobilization of CD34+CD31+ EPCs into the blood, as compared with a G-CSF bolus injection or hydrogel injection only. In addition, AMD3100, an antagonist of CXCR4, has been used singly or in combination with G-CSF to enhance mobilization of HSCs and progenitor cells.45 Another report describes the use of AMD injection for the treatment of myocardial infarction. AMD treatment enhanced mobilization and recruitment of EPCs to the neovasculature.46 In addition, a combined treatment of G-CSF and AMD has resulted in efficient mobilization of monocytes and stimulation of angiogenesis at ischemic sites.47

Stem cell factor is an endogenous ligand for the tyrosine kinase receptor c-kit, which is expressed on HSCs. Recombinant stem cell factor has been shown to act in synergy with G-CSF in mobilization of bone marrow-derived HSCs.48 Regulation of selective mobilization of different populations of stem cells has been tested.49 This study showed that treatment with CXCR4 antagonist (AMD3100) effectively mobilizes HSCs, but not EPCs or stromal cells. However, pretreatment with vascular endothelial growth factor (VEGF) resulted in EPC and stromal cell mobilization, whereas HSC mobilization was reduced. These results suggest that multiple intersecting signaling pathways regulate the proliferation and mobilization of bone marrow-derived stem cells for efficacious tissue regeneration.

Direct targeting of the stem cell niche is another approach to induce stem cell mobilization for promoting tissue regeneration. In bone marrow, one component of the HSC niche is osteoblasts. It was shown that stimulation of the parathyroid hormone receptor promotes osteoblast proliferation and secretion of paracrine factors that, in turn, resulted in an increase in the number of HSCs.50 These studies indicate that direct targeting of osteoblasts can modify the activity of HSCs in the bone marrow.

In addition to stem cell-stimulating factors that mobilize host stem/progenitor cells in the body, bioactive molecules that induce engraftment of the mobilized host stem cells into desired tissues or organs for repair are considered as important cues for efficient in situ tissue regeneration.51 One representative chemoattractant is SDF-1α that has been shown to attract MSCs52 and HSCs to injured tissues through CXCR4 (SDF-1 receptor) expression.53 In peripheral blood where the expression of CXCR4 is at a low level, a pool of both MSCs and HSCs can be maintained at a balanced level in distant parts of the body. However, tissue damage or other mobilization cues could mobilize these cells to peripheral blood and to the injury site. Thus, it is possible that sustained release of chemoattractants such as SDF-1α contained within an implanted scaffold could generate a high concentration gradient of these factors and drive efficient stem cell migration into the implant. For example, a previous report showed that local release of SDF-1α was observed from heparinized collagen sponge-enhanced recruitment of HSCs into subcutaneously implanted scaffolds. One recent study demonstrated an interesting approach to utilize the effects of SDF-1α on recruitment of host stem cell into implanted scaffolds.54 This group incorporated SDF-1α into a biodegradable PLGA scaffold and implanted subcutaneously in mice. They showed that local release of SDF-1α induced efficient recruitment of host stem cells (SSEA-4+ cells) in the implanted scaffold. In addition, the scaffolding system resulted in a reduced inflammatory response. This approach has also been applied to brain injury for the recruitment of neural progenitor cells.55 For accelerated brain regeneration from cavitary brain lesions that fail to recruit endogenous neural progenitor cells, the authors developed an injectable scaffolding system that consists of gelatin-hydroxyphenylpropionic acid hydrogels and dextran sulfate/chitosan polyelectrolyte complex nanoparticles to deliver SDF-1α to the cavitary brain lesion region. They demonstrated the initial feasibility in vitro by showing that release of SDF-1α from the incorporated gel scaffold system significantly enhanced infiltration of neural progenitor cells, when compared with hydrogel only or vehicle controls, indicating that this scaffolding system is a promising approach for neural tissue repair.

SDF-1α is known to be easily damaged by matrix metalloproteinase-2. To address this issue, SDF-1α molecule was engineered to be resistant to protease activity and the engineered SDF-1α was tethered to self-assembling peptides to form nanofibers.56 In this study the authors showed that the injected nanofibers containing protease-resistant SDF-1α molecules enhanced recruited EPCs, increased capillary density and functionally improved cardiac function. In an attempt to protect SDF-1α effects from endogenous inhibitors, an alternative approach showed that targeting of SDF-1α inhibitor improved SDF-1α effectiveness in stem cell engraftment into the damaged heart.57 The dipeptidyl peptidase IV is known to cleave SDF-1α, therefore inhibition of dipeptidyl peptidase IV by the small-molecule diprotin A increases the concentration of SDF-1α in the heart following myocardial infarction. This resulted in increased progenitor cell recruitment to the ischemic myocardium and improved neovascularization and ventricular function.57 Targeting of these inhibitors represents an effective strategy for regenerative medicine.

Monocyte chemotactic proteins (MCPs) are known to direct bone marrow-derived stem cells into the injury sites. One study shows that MCP-3 recruits MSCs into myocardial infarction site through activation of CC chemokine receptors.58 In addition, MCP-1 and MCP-5 have been reported to be CCR2-activating chemokines that recruit bone marrow-derived macrophages into toxin-induced muscle injury site to restore angiogenesis and muscle regeneration.59 A neuropeptide, galanin, has also been identified to play an important role in facilitating bone marrow-derived MSC migration through activation of galanin receptor.60

Protein delivery system

When bioactive molecules are administered into the injury site as a bolus injection, most of the factors tend to lose their biological activities because of enzymatic digestion in the body. To overcome this limitation and maintain effective concentrations of molecules in the local microenvironment, sustained release of bioactive cues can be accomplished by encapsulation within a scaffolding system through physical or chemical binding. Release pattern of the incorporated bioactive factors can be controlled by scaffold modifications through changing physical properties, temperature, pH and material degradability. In particular, a scaffolding system for in situ tissue regeneration needs to possess an appropriate microenvironment that is able to recruit host stem and progenitor cells into the implant and support the expansion and differentiation into a desired tissue type. For this purpose, multiple factors need to be delivered to a target site because of the complexity of the microenvironment. In one study, a multiple protein delivery system was developed for accelerating vascularization and functional tissue formation, based on the fact that functional regeneration of tissues and organs is typically induced by the action of a number of growth factors.61 The investigators reported that a new polymeric system facilitated the tissue-specific delivery of two or more growth factors, and enabled sustained release of bioactive molecules with different release kinetics for effective tissue regeneration. Similarly, a recent study demonstrated various delivery methods of bioactive molecules for controlled release over time.62 Sustained release of multiple molecules mimics in vivo tissue regeneration and it contributes to effective and functional tissue regeneration. Another study used a gelatin-based scaffold to deliver four different bioactive molecules, namely VEGF, angiopoietin-1, keratinocyte growth factor and platelet-derived growth factor-BB.63 The delivery of these molecules induced an increase in angiogenesis with a potential for promoting tissue regeneration.63 However, the current delivery systems are limited to local delivery via release from the implanted scaffold62 that results in accumulation of migrated cells mostly at the periphery of the scaffold, delaying cell infiltration into the interior of the scaffold. Consequently, the unbalanced cell localization prevents successful tissue regeneration. It is evident that a new delivery approach that facilitates efficient recruitment of host stem cells needs to be developed.

Toward this goal, we have developed a new delivery method, in which combined systemic and local delivery of multiple factors (SP and SDF-1α) were used to enhance recruitment of host stem cells such as MSC and HSC populations from two different compartiments (circulating bloods and resident sources) into target scaffolds in vivo.64 This strategy (Figure 3) consists of two steps: (1) to increase mobilization of bone marrow-derived MSCs and HSCs by systemic SP injection and (2) to enhance recruitment of two different populations of the SP-stimulated bone marrow-derived cells and resident stem cells into the implanted scaffolds via local release of SDF-1α from the scaffolds. Our results showed that this combination delivery system significantly enhanced host stem cells such as CD29+CD45- MSC-like cells, CD146+a-SMA+ pericytes and c-kit+ cell-included HSC population into the scaffolding system, indicating the effectiveness of the combination delivery system for in situ tissue regeneration.

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Combination delivery system that uses systemic (a stem cell-stimulating factor, substance P (SP)) and local delivery (stem cell migrating factor, stromal cell-derived factor-1α (SDF-1α)); (ac) CD29+CD45 mesenchymal stem cell (MSC)-like cells and (df) CD146+α-SMA+ pericyte recruitment by the combination delivery system.64 α-SMA, α-smooth muscle actin; RBC, red blood cells.

Full figure and legend (277K)

Top

Applications of in situ tissue regeneration

The concept of in situ tissue regeneration has been translated into various therapeutic applications (Table 2). Various biomaterial scaffolds have been used for this purpose in the form of injection or implantation. Although many technologies are at the early stage in investigations, several technologies have been successfully performed in preclinical animal models and clinical applications with satisfactory outcomes.


Bone

Osteogenic repair from bone loss has benefited from techniques of in situ tissue regeneration.65 The required properties for a bone-specific scaffold are temporal and mechanical load bearing within the tissue defects. Moreover, it should minimize immune and/or inflammatory response. Biomaterials widely used for in situ bone regeneration include calcium phosphate, calcium sulfate and hydroxyapatite. As bone tissue is composed of these materials, it would be natural to consider using such materials for scaffolds for bone regeneration. This is because of their close chemical and crystal resemblance to the mineral phase of bone, demonstrating excellent biocompatibility and osteoconductivity.66, 67 The commonly used bioactive molecules for bone regeneration include bone morphogenetic protein-2, transforming growth factor-β, basic fibroblast growth factor and VEGF. In some cases, vital growth factors can be incorporated into the scaffolds to exert their osteoinductive and vascularization properties.68, 69, 70 Biomaterials ranging from natural polymers, such as alginate, fibrin or gelatin, to synthetic polymers, such as poly(lactic acid) and PLGA, have been fabricated with either single or multiple bioactive molecules.71 These scaffolds have demonstrated an ability to stimulate and induce neighboring bone marrow stromal cells and enhance bone tissue formation. Many clinical applications have been conducted for bone regeneration in situ using calcium phosphate cements, collagen gel or sponge combined with clinically approved bone morphogenetic protein-2.72, 73, 74

Cartilage

Injured and damaged cartilage tissue can lead to severe arthritis because of low natural healing capability when compared with other types of tissues. In early studies, cartilage tissue constructs were easily produced by seeding chondrocytes onto scaffolds. However, when engineered cartilage constructs are implanted, a serious compatibility issue such as poor integration with the host tissue is often observed. As such, a recent study showed that successful cartilage regeneration can be achieved using a cell-free scaffolding system. In this study, scaffolds consisting of biodegradable PLGA polymer were incorporated with plasma and hyaluronic acid, and implanted into microfractured cartilage tissue.75 Consequently, the implanted constructs facilitated the migration of bone marrow-derived stem cells that led to the formation of neo-cartilage tissue. More recently, Lee et al.76 demonstrated that an entire articular surface of the synovial joint can be regenerated without cell transplantation using three-dimensional poly(ε-caprolactone) and hydroxyapatite composites fabricated by solid free-form technique. These scaffolds were incorporated with transforming growth factor-β3 and implanted into a rabbit model. Regeneration of new and avascular cartilage with vascularized subchondral bone tissue was evident. This result was shown to be effective in regenerating cartilage tissue by recruiting host stem cells to the site of the implants.76

Skeletal muscle

Muscle tissue is the largest tissue mass in the body. Skeletal muscle accounts for ~45% of total body weight. Skeletal muscle tissue contains bundles of myofibers that function by contracting with motor nerve stimulation. Minor muscle injury because of exercise and weight lifting is easily restored by natural regenerative processes. However, if >20% of the muscle is lost, spontaneous recovery will not occur, leading to loss of muscle function. If the injury is not properly treated, skeletal muscle weakness and atrophy will occur.77

Cell-based approaches have offered new opportunities for restoring muscle function because of severe muscular injuries. Muscle satellite cells78, 79 have been identified as a cell source for muscle tissue regeneration owing to their self-renewal capabilities and muscle-specific differentiation following muscle injury. In addition to muscle satellite cells, several other stem cell populations, such as muscle-derived stem cells,80 pericytes,81 muscle-resident macrophages,82, 83 EPCs53 and bone marrow-derived MSCs84 have been used for muscle tissue engineering. The roles of these cell populations are critical for efficient muscle regeneration, by promoting angiogenesis and maturing neovasculatures, secreting myogenic trophic factors and modulating inflammation for reduced fibrosis.82, 85

Several studies have been performed to regenerate muscle tissue in situ.86 In one study, an alginate gel-based dual delivery system was used to deliver insulin-like growth factor-1 and VEGF for the enhancement of functional muscle regeneration. The roles of sustained release of insulin-like growth factor-1 and VEGF from the scaffold are mobilization and manipulation of satellite cells and inducing efficient angiogenesis for functional muscle regeneration, respectively. In another study, a collagen-based sponge scaffold was used to treat rabbit hind limb muscle injury. At 24 weeks after implantation, the control group (without scaffold) showed poor structural regeneration with severe scar tissue formation at the site of injury, whereas the scaffold-implanted group showed mild focal adhesions and new muscle tissue formation.87 One important consideration for muscle regeneration in situ is how to create aligned and organized muscle fibers within the implanted scaffold. Alignment is critical for newly regenerated muscle fibers to exert normal physiological muscle function in response to nerve stimulation. Recently, a scaffolding system consisting of unidirectionally aligned fibers was developed by electrospinning techniques using poly(ε-caprolactone) and collagen as base materials.36 When skeletal muscle cells were seeded on the scaffolds, cellular alignment along the polymer fibers was evident with formation of organized muscle fibers upon differentiation. This result indicates that fabrication of muscle-specific scaffolds may be important for in situ muscle tissue regeneration.

Top

Conclusions

In situ tissue regeneration holds great potential to provide new therapeutic options for functional tissue regeneration. In order for this approach to be successful, stem cells need to be directed to the target sites, and appropriately guided to proliferate and differentiate into the cell type of interest within the microenvironment provided by biomaterial scaffolds. A variety of tissue-specific biomaterials and bioactive molecules have been identified and combined to promote stem and progenitor cell mobilization. As such, the concept of in situ tissue regeneration has been demonstrated in multiple tissue systems. However, continued development of effective tissue-specific scaffolding systems that provide powerful cues for stem cell activation and recruitment is needed in order to achieve functional tissue regeneration in situ. A better understanding of the complex interactions and pathways of the biomolecules that are involved in the targeted tissue regeneration is necessary in order to achieve effective therapeutic outcomes for translation into the clinic.

Top

Conflict of interest

The authors declare no conflict of interest.

Top

References

  1. Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma 1989; 3: 192–195. | Article | PubMed | CAS |
  2. Grogan BF, Hsu JR. Volumetric muscle loss. J Am Acad Orthop Surg 2011; 19(Suppl. 1): S35–S37. | PubMed |
  3. Atala A. Engineering tissues, organs and cells. J Tissue Eng Regen Med 2007; 1: 83–96. | Article | PubMed | CAS |
  4. Lutolf MP, Gilbert PM, Blau HM. Designing materials to direct stem-cell fate. Nature 2009; 462: 433–441. | Article | PubMed | ISI | CAS |
  5. Green EM, Lee RT. Proteins and small molecules for cellular regenerative medicine. Physiol Rev 2013; 93: 311–325. | Article | PubMed |
  6. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964–967. | Article | PubMed | ISI | CAS |
  7. Bartsch G, Yoo JJ, De Coppi P, Siddiqui MM, Schuch G, Pohl HG et al. Propagation, expansion, and multilineage differentiation of human somatic stem cells from dermal progenitors. Stem Cells Dev 2005; 14: 337–348. | Article | PubMed | ISI | CAS |
  8. De Ugarte DA, Ashjian PH, Elbarbary A, Hedrick MH. Future of fat as raw material for tissue regeneration. Ann Plast Surg 2003; 50: 215–219. | Article | PubMed |
  9. Deasy BM, Huard J. Gene therapy and tissue engineering based on muscle-derived stem cells. Curr Opin Mol Ther 2002; 4: 382–389. | PubMed |
  10. Gage FH. Mammalian neural stem cells. Science 2000; 287: 1433–1438. | Article | PubMed | ISI | CAS |
  11. Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A et al. CD31- but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 2005; 97: 52–61. | Article | PubMed | ISI | CAS |
  12. Zhang Y, Bai XF, Huang CX. Hepatic stem cells: existence and origin. World J Gastroenterol 2003; 9: 201–204. | PubMed | ISI |
  13. Dahlberg A, Delaney C, Bernstein ID. ex vivo expansion of human hematopoietic stem and progenitor cells. Blood 2011; 117: 6083–6090. | Article | PubMed |
  14. Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 2007; 213: 341–347. | Article | PubMed | ISI | CAS |
  15. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell 2011; 9: 11–15. | Article | PubMed | CAS |
  16. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 953–964. | Article | PubMed | ISI | CAS |
  17. Badylak SF, Valentin JE, Ravindra AK, McCabe GP, Stewart-Akers AM. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng Part A. 2008; 14: 1835–1842. | Article | PubMed |
  18. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004; 25: 677–686. | Article | PubMed | ISI | CAS |
  19. Lee SJ, Van Dyke M, Atala A, Yoo JJ. Host cell mobilization for in situ tissue regeneration. Rejuvenation Res 2008; 11: 747–756. | Article | PubMed |
  20. Lutolf MP, Hubbell JA. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol 2005; 23: 47–55. | Article | PubMed | ISI | CAS |
  21. Lee KY, Jeong L, Kang YO, Lee SJ, Park WH. Electrospinning of polysaccharides for regenerative medicine. Adv Drug Deliv Rev 2009; 61: 1020–1032. | Article | PubMed |
  22. Cen L, Liu W, Cui L, Zhang W, Cao Y. Collagen tissue engineering: development of novel biomaterials and applications. Pediatr Res 2008; 63: 492–496. | Article | PubMed |
  23. Cavallaro JF, Kemp PD, Kraus KH. Collagen fabrics as biomaterials. Biotechnol Bioeng 1994; 44: 146. | Article | PubMed |
  24. Yannas IV, Burke JF. Design of an artificial skin. I. Basic design principles. J Biomed Mater Res 1980; 14: 65–81. | Article | PubMed | ISI | CAS |
  25. Yannas IV, Burke JF, Gordon PL, Huang C, Rubenstein RH. Design of an artificial skin. II. Control of chemical composition. J Biomed Mater Res 1980; 14: 107–132. | Article | PubMed |
  26. Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 2010; 16: 927–933. | Article | PubMed | ISI | CAS |
  27. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 2008; 14: 213–221. | Article | PubMed | ISI | CAS |
  28. Badylak SF. Regenerative medicine and developmental biology: the role of the extracellular matrix. Anat Rec B New Anat 2005; 287: 36–41. | PubMed |
  29. Gilding D. Biodegradable polymers. In: Williams D ed. Biocompatibility of Clinical Implant Materials. CRC Press: Boca Raton, FL, 1981, 209–232.
  30. Freed LE, Vunjak-Novakovic G, Biron RJ, Eagles DB, Lesnoy DC, Barlow SK et al. Biodegradable polymer scaffolds for tissue engineering. Biotechnology (NY) 1994; 12: 689–693. | Article | CAS |
  31. Mikos AG, Lyman MD, Freed LE, Langer R. Wetting of poly(L-lactic acid) and poly(DL-lactic-co-glycolic acid) foams for tissue culture. Biomaterials 1994; 15: 55–58. | Article | PubMed |
  32. Han D, Gouma PI. Electrospun bioscaffolds that mimic the topology of extracellular matrix. Nanomedicine 2006; 2: 37–41. | Article | PubMed | CAS |
  33. Harris LD, Kim BS, Mooney DJ. Open pore biodegradable matrices formed with gas foaming. J Biomed Mater Res 1998; 42: 396–402. | Article | PubMed | ISI | CAS |
  34. Lee SJ, Liu J, Oh SH, Soker S, Atala A, Yoo JJ. Development of a composite vascular scaffolding system that withstands physiological vascular conditions. Biomaterials 2008; 29: 2891–2898. | Article | PubMed | CAS |
  35. Lee SJ, Oh SH, Liu J, Soker S, Atala A, Yoo JJ. The use of thermal treatments to enhance the mechanical properties of electrospun poly(epsilon-caprolactone) scaffolds. Biomaterials 2008; 29: 1422–1430. | Article | PubMed |
  36. Choi JS, Lee SJ, Christ GJ, Atala A, Yoo JJ. The influence of electrospun aligned poly(epsilon-caprolactone)/collagen nanofiber meshes on the formation of self-aligned skeletal muscle myotubes. Biomaterials 2008; 29: 2899–2906. | Article | PubMed | ISI |
  37. Peppas NA, Langer R. New challenges in biomaterials. Science 1994; 263: 1715–1720. | Article | PubMed | ISI | CAS |
  38. Hong HS, Lee J, Lee E, Kwon YS, Ahn W, Jiang MH et al. A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells. Nat Med 2009; 15: 425–435. | Article | PubMed |
  39. Hong HS, Kim do Y, Yoon KJ, Son Y. A new paradigm for stem cell therapy: substance-P as a stem cell-stimulating agent. Arch Pharm Res 2011; 34: 2003–2006. | Article | PubMed |
  40. Amadesi S, Reni C, Katare R, Meloni M, Oikawa A, Beltrami AP et al. Role for substance p-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects. Circulation 2012; 125: 1774–1786 S1-19. | Article | PubMed |
  41. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 1997; 185: 111–120. | Article | PubMed | ISI | CAS |
  42. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002; 3: 687–694. | Article | PubMed | ISI | CAS |
  43. Zhou M, Liu Z, Li K, Qiao W, Jiang X, Ran F et al. Beneficial effects of granulocyte-colony stimulating factor on small-diameter heparin immobilized decellularized vascular graft. J Biomed Mater Res A. 2010; 95: 600–610. | PubMed |
  44. Liang Y, Jensen TW, Roy EJ, Cha C, Devolder RJ, Kohman RE et al. Tuning the non-equilibrium state of a drug-encapsulated poly(ethylene glycol) hydrogel for stem and progenitor cell mobilization. Biomaterials 2011; 32: 2004–2012. | Article | PubMed |
  45. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005; 201: 1307–1318. | Article | PubMed | ISI | CAS |
  46. Jujo K, Hamada H, Iwakura A, Thorne T, Sekiguchi H, Clarke T et al. CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction. Proc Natl Acad Sci USA 2010; 107: 11008–11013. | Article | PubMed |
  47. Capoccia BJ, Shepherd RM, Link DC. G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. Blood 2006; 108: 2438–2445. | Article | PubMed | ISI |
  48. McNiece IK, Briddell RA. Stem cell factor. J Leukoc Biol 1995; 58: 14–22. | PubMed | ISI | CAS |
  49. Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009; 4: 62–72. | Article | PubMed | ISI | CAS |
  50. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003; 425: 841–846. | Article | PubMed | ISI | CAS |
  51. Vanden Berg-Foels WS. in situ tissue regeneration: chemoattractants for endogenous stem cell recruitment. Tissue Eng Part B Rev, (doi:10.1089/ten.teb.2013.0100). | Article |
  52. Lau TT, Wang DA. Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine. Expert Opin Biol Ther 2011; 11: 189–197. | Article | PubMed |
  53. Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 2006; 12: 557–567. | Article | PubMed | ISI | CAS |
  54. Thevenot PT, Nair AM, Shen J, Lotfi P, Ko CY, Tang L. The effect of incorporation of SDF-1alpha into PLGA scaffolds on stem cell recruitment and the inflammatory response. Biomaterials 2010; 31: 3997–4008. | Article | PubMed |
  55. Lim TC, Rokkappanavar S, Toh WS, Wang LS, Kurisawa M, Spector M. Chemotactic recruitment of adult neural progenitor cells into multifunctional hydrogels providing sustained SDF-1alpha release and compatible structural support. FASEB J. 2013; 27: 1023–1033. | Article | PubMed |
  56. Segers VF, Tokunou T, Higgins LJ, MacGillivray C, Gannon J, Lee RT. Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation 2007; 116: 1683–1692. | Article | PubMed | ISI | CAS |
  57. Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 2009; 4: 313–323. | Article | PubMed | CAS |
  58. Schenk S, Mal N, Finan A, Zhang M, Kiedrowski M, Popovic Z et al. Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells 2007; 25: 245–251. | Article | PubMed |
  59. Martinez CO, McHale MJ, Wells JT, Ochoa O, Michalek JE, McManus LM et al. Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment. Am J Physiol Regul Integr Comp Physiol 2010; 299: R832–R842. | Article | PubMed |
  60. Louridas M, Letourneau S, Lautatzis ME, Vrontakis M. Galanin is highly expressed in bone marrow mesenchymal stem cells and facilitates migration of cells both in vitro and in vivo. Biochem Biophys Res Commun 2009; 390: 867–871. | Article | PubMed |
  61. Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat Biotechnol 2001; 19: 1029–1034. | Article | PubMed | ISI | CAS |
  62. Chen FM, Zhang M, Wu ZF. Toward delivery of multiple growth factors in tissue engineering. Biomaterials 2010; 31: 6279–6308. | Article | PubMed | CAS |
  63. Elia R, Fuegy PW, VanDelden A, Firpo MA, Prestwich GD, Peattie RA. Stimulation of in vivo angiogenesis by in situ crosslinked, dual growth factor-loaded, glycosaminoglycan hydrogels. Biomaterials 2010; 31: 4630–4638. | Article | PubMed |
  64. Ko IK, Ju YM, Chen T, Atala A, Yoo JJ, Lee SJ. Combined systemic and local delivery of stem cell inducing/recruiting factors for in situ tissue regeneration. FASEB J. 2012; 26: 158–168. | Article | PubMed |
  65. Mistry AS, Mikos AG. Tissue engineering strategies for bone regeneration. Adv Biochem Eng Biotechnol 2005; 94: 1–22. | PubMed |
  66. Piacquadio D, Jarcho M, Goltz R. Evaluation of hylan b gel as a soft-tissue augmentation implant material. J Am Acad Dermatol 1997; 36: 544–549. | Article | PubMed | CAS |
  67. Jarcho M, Kay JF, Gumaer KI, Doremus RH, HP Drobeck. Tissue, cellular and subcellular events at a bone-ceramic hydroxylapatite interface. J Bioeng 1977; 1: 79–92. | PubMed |
  68. Ginebra MP, Traykova T, Planell JA. Calcium phosphate cements as bone drug delivery systems: a review. J Control Release 2006; 113: 102–110. | Article | PubMed |
  69. Jansen JA, Vehof JW, Ruhe PQ, Kroeze-Deutman H, Kuboki Y, Takita H et al. Growth factor-loaded scaffolds for bone engineering. J Control Release 2005; 101: 127–136. | Article | PubMed |
  70. Seeherman H, Wozney JM. Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev 2005; 16: 329–345. | Article | PubMed | CAS |
  71. Woo BH, Jiang G, Jo YW, DeLuca PP. Preparation and characterization of a composite PLGA and poly(acryloyl hydroxyethyl starch) microsphere system for protein delivery. Pharm Res 2001; 18: 1600–1606. | Article | PubMed |
  72. Barnes B, Boden SD, Louis-Ugbo J, Tomak PR, Park JS, Park MS et al. Lower dose of rhBMP-2 achieves spine fusion when combined with an osteoconductive bulking agent in non-human primates. Spine (Phila Pa 1976). 2005; 30: 1127–1133. | Article | PubMed |
  73. Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002; 27: 2396–2408. | Article | PubMed |
  74. Geesink RG, Hoefnagels NH, Bulstra SK. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg Br 1999; 81: 710–718. | Article | PubMed | CAS |
  75. Erggelet C, Endres M, Neumann K, Morawietz L, Ringe J, Haberstroh K et al. Formation of cartilage repair tissue in articular cartilage defects pretreated with microfracture and covered with cell-free polymer-based implants. J Orthop Res 2009; 27: 1353–1360. | Article | PubMed |
  76. Lee CH, Cook JL, Mendelson A, Moioli EK, Yao H, Mao JJ. Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study. Lancet 2010; 376: 440–448. | Article | PubMed | CAS |
  77. Huard J, Li Y, Fu FH. Muscle injuries and repair: current trends in research. J Bone Joint Surg Am 2002; 84-A(5: 822–832.
  78. Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM. Self-renewal and expansion of single transplanted muscle stem cells. Nature 2008; 456: 502–506. | Article | PubMed | ISI | CAS |
  79. Le Grand F, Rudnicki MA. Skeletal muscle satellite cells and adult myogenesis. Curr Opin Cell Biol 2007; 19: 628–633. | Article | PubMed | ISI | CAS |
  80. Qu-Petersen Z, Deasy B, Jankowski R, Ikezawa M, Cummins J, Pruchnic R et al. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J Cell Biol 2002; 157: 851–864. | Article | PubMed | ISI | CAS |
  81. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008; 3: 301–313. | Article | PubMed | ISI | CAS |
  82. Sun D, Martinez CO, Ochoa O, Ruiz-Willhite L, Bonilla JR, Centonze VE et al. Bone marrow-derived cell regulation of skeletal muscle regeneration. FASEB J. 2009; 23: 382–395. | Article | PubMed |
  83. Polesskaya A, Seale P, Rudnicki MA. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell 2003; 113: 841–852. | Article | PubMed | ISI | CAS |
  84. LaBarge MA, Blau HM. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 2002; 111: 589–601. | Article | PubMed | ISI | CAS |
  85. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 2009; 20: 419–427. | Article | PubMed | CAS |
  86. Borselli C, Storrie H, Benesch-Lee F, Shvartsman D, Cezar C, Lichtman JW et al. Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors. Proc Natl Acad Sci USA 2010; 107: 3287–3292. | Article | PubMed |
  87. Kin S, Hagiwara A, Nakase Y, Kuriu Y, Nakashima S, Yoshikawa T et al. Regeneration of skeletal muscle using in situ tissue engineering on an acellular collagen sponge scaffold in a rabbit model. ASAIO J. 2007; 53: 506–513. | Article | PubMed |
  88. Suzuki Y, Tanihara M, Suzuki K, Saitou A, Sufan W, Nishimura Y. Alginate hydrogel linked with synthetic oligopeptide derived from BMP-2 allows ectopic osteoinduction in vivo. J Biomed Mater Res 2000; 50: 405–409. | Article | PubMed |
  89. Woodruff MA, Rath SN, Susanto E, Haupt LM, Hutmacher DW, Nurcombe V et al. Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model. J Mol Histol 2007; 38: 425–433. | Article | PubMed |
  90. Kodama N, Nagata M, Tabata Y, Ozeki M, Ninomiya T, Takagi R. A local bone anabolic effect of rhFGF2-impregnated gelatin hydrogel by promoting cell proliferation and coordinating osteoblastic differentiation. Bone 2009; 44: 699–707. | Article | PubMed | ISI | CAS |
  91. Yamamoto M, Takahashi Y, Tabata Y. Enhanced bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel. Tissue Eng 2006; 12: 1305–1311. | Article | PubMed |
  92. Osathanon T, Linnes ML, Rajachar RM, Ratner BD, Somerman MJ, Giachelli CM. Microporous nanofibrous fibrin-based scaffolds for bone tissue engineering. Biomaterials 2008; 29: 4091–4099. | Article | PubMed |
  93. Haidar ZS, Hamdy RC, Tabrizian M. Biocompatibility and safety of a hybrid core-shell nanoparticulate OP-1 delivery system intramuscularly administered in rats. Biomaterials 2010; 31: 2746–2754. | Article | PubMed |
  94. Mabilleau G, Aguado E, Stancu IC, Cincu C, Basle MF, Chappard D. Effects of FGF-2 release from a hydrogel polymer on bone mass and microarchitecture. Biomaterials 2008; 29: 1593–1600. | Article | PubMed |
  95. Erggelet C, Neumann K, Endres M, Haberstroh K, Sittinger M, Kaps C. Regeneration of ovine articular cartilage defects by cell-free polymer-based implants. Biomaterials 2007; 28: 5570–5580. | Article | PubMed |
  96. Kubo M, Imai S, Fujimiya M, Isoya E, Ando K, Mimura T et al. Exogenous collagen-enhanced recruitment of mesenchymal stem cells during rabbit articular cartilage repair. Acta Orthop 2007; 78: 845–855. | Article | PubMed |
  97. Matsumura G, Isayama N, Matsuda S, Taki K, Sakamoto Y, Ikada Y et al. Long-term results of cell-free biodegradable scaffolds for in situ tissue engineering of pulmonary artery in a canine model. Biomaterials 2013; 34: 6422–6428. | Article | PubMed |
  98. Salimath AS, Phelps EA, Boopathy AV, Che PL, Brown M, Garcia AJ et al. Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats. PLoS One 2012; 7: e50980. | Article | PubMed |
  99. Zheng W, Wang Z, Song L, Zhao Q, Zhang J, Li D et al. Endothelialization and patency of RGD-functionalized vascular grafts in a rabbit carotid artery model. Biomaterials 2012; 33: 2880–2891. | Article | PubMed |
  100. De Visscher G, Mesure L, Meuris B, Ivanova A, Flameng W. Improved endothelialization and reduced thrombosis by coating a synthetic vascular graft with fibronectin and stem cell homing factor SDF-1alpha. Acta Biomater 2012; 8: 1330–1338. | Article | PubMed |
  101. Kuwabara F, Narita Y, Yamawaki-Ogata A, Kanie K, Kato R, Satake M et al. Novel small-caliber vascular grafts with trimeric peptide for acceleration of endothelialization. Ann Thorac Surg 2012; 93: 156–163 discussion 63. | Article | PubMed |
  102. Jordan JE, Williams JK, Lee SJ, Raghavan D, Atala A, Yoo JJ. Bioengineered self-seeding heart valves. J Thorac Cardiovasc Surg 2012; 143: 201–208. | Article | PubMed |
  103. Iwai S, Sawa Y, Taketani S, Torikai K, Hirakawa K, Matsuda H. Novel tissue-engineered biodegradable material for reconstruction of vascular wall. Ann Thorac Surg 2005; 80: 1821–1827. | Article | PubMed |
  104. Yokota T, Ichikawa H, Matsumiya G, Kuratani T, Sakaguchi T, Iwai S et al. in situ tissue regeneration using a novel tissue-engineered, small-caliber vascular graft without cell seeding. J Thorac Cardiovasc Surg 2008; 136: 900–907. | Article | PubMed |
  105. Huynh T, Abraham G, Murray J, Brockbank K, Hagen PO, Sullivan S. Remodeling of an acellular collagen graft into a physiologically responsive neovessel. Nat Biotechnol 1999; 17: 1083–1086. | Article | PubMed | CAS |
  106. Fujimoto KL, Tobita K, Merryman WD, Guan J, Momoi N, Stolz DB et al. An elastic, biodegradable cardiac patch induces contractile smooth muscle and improves cardiac remodeling and function in subacute myocardial infarction. J Am Coll Cardiol 2007; 49: 2292–2300. | Article | PubMed |
  107. Fujimoto KL, Guan J, Oshima H, Sakai T, Wagner WR. in vivo evaluation of a porous, elastic, biodegradable patch for reconstructive cardiac procedures. Ann Thorac Surg 2007; 83: 648–654. | Article | PubMed |
  108. Landa N, Miller L, Feinberg MS, Holbova R, Shachar M, Freeman I et al. Effect of injectable alginate implant on cardiac remodeling and function after recent and old infarcts in rat. Circulation 2008; 117: 1388–1396. | Article | PubMed | CAS |
  109. Dahms SE, Piechota HJ, Dahiya R, Gleason CA, Hohenfellner M, Tanagho EA. Bladder acellular matrix graft in rats: its neurophysiologic properties and mRNA expression of growth factors TGF-alpha and TGF-beta. Neurourol Urodyn 1998; 17: 37–54. | Article | PubMed |
  110. Urita Y, Komuro H, Chen G, Shinya M, Kaneko S, Kaneko M et al. Regeneration of the esophagus using gastric acellular matrix: an experimental study in a rat model. Pediatr Surg Int 2007; 23: 21–26. | Article | PubMed |
  111. Boucard N, Viton C, Agay D, Mari E, Roger T, Chancerelle Y et al. The use of physical hydrogels of chitosan for skin regeneration following third-degree burns. Biomaterials 2007; 28: 3478–3488. | Article | PubMed | CAS |
  112. Abbushi A, Endres M, Cabraja M, Kroppenstedt SN, Thomale UW, Sittinger M et al. Regeneration of intervertebral disc tissue by resorbable cell-free polyglycolic acid-based implants in a rabbit model of disc degeneration. Spine (Phila Pa 1976). 2008; 33: 1527–1532. | Article | PubMed |
  113. Hori Y, Nakamura T, Matsumoto K, Kurokawa Y, Satomi S, Shimizu Y. Experimental study on in situ tissue engineering of the stomach by an acellular collagen sponge scaffold graft. ASAIO J. 2001; 47: 206–210. | Article | PubMed |
  114. Nakahara T, Nakamura T, Kobayashi E, Inoue M, Shigeno K, Tabata Y et al. Novel approach to regeneration of periodontal tissues based on in situ tissue engineering: effects of controlled release of basic fibroblast growth factor from a sandwich membrane. Tissue Eng 2003; 9: 153–162. | Article | PubMed |
  115. Herberg S, Siedler M, Pippig S, Schuetz A, Dony C, Kim CK et al. Development of an injectable composite as a carrier for growth factor-enhanced periodontal regeneration. J Clin Periodontol 2008; 35: 976–984. | Article | PubMed |
Top

Acknowledgements

We thank Dr John D Jackson for editorial assistance. This work was supported, in part, by the Armed Forces Institute for Regenerative Medicine (W81XWH-08-2-0032).

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.