In vitro analog of human bone marrow from 3D scaffolds with biomimetic inverted colloidal crystal geometry

Nichols, Joan E.; Cortiella, Joaquin; Lee, Jungwoo; Niles, Jean A.; Cuddihy, Meghan; Wang, Shaopeng; Bielitzki, Joseph T.; Cantu, Andrea; Mlcak, Ron; Valdivia, Esther; Yancy, Ryan; McClure, Matthew L.; Kotov, Nicholas A.

doi:10.1016/j.biomaterials.2008.10.041

Cited by 132 publications

(113 citation statements)

References 58 publications

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“…3 a,b). Thus, the long-term HSCs, which are the only cells capable of long-term self-renewal and multi-lineage potential, appear to be differentiating into more specialized progenitor cells in the static stromasupported cultures system, as previously reported [6][7][8][9] . In contrast, the number and distribution of HSCs and hematopoietic progenitor cells in the eBM cultured for up to 7 days on-chip were maintained in similar proportions to freshly harvested bone marrow (Fig.…”

Section: In Vitro Culture Of Engineered Bone Marrowsupporting

confidence: 71%

“…Engineering an artificial bone marrow that reconstitutes natural marrow structure and function, and that can be maintained in culture, could be a powerful platform to study hematopoiesis and test new therapeutics. It has proven difficult, however, to recreate the complex bone marrow microenvironment needed to support the formation and maintenance of a complete, functional hematopoietic niche in vitro [6][7][8][9] . Although various in vitro culture systems have (Revised NMETH-A19608) been developed to maintain and expand hematopoietic stem and progenitor cells 6-11 , there is currently no method to recreate or study the intact bone marrow microenvironment in vitro.…”

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confidence: 99%

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Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro

et al. 2014

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____________________________________________________________________________The bone marrow microenvironment contains a complex set of cellular, chemical, structural and physical cues necessary to maintain the viability and function of the hematopoietic system [1][2][3][4][5] . This hematopoietic niche regulates hematopoietic stem cells (HSCs), facilitating a delicate balance between self-renewal and differentiation into progenitor cells that produce all mature blood cell types 4,5 . Engineering an artificial bone marrow that reconstitutes natural marrow structure and function, and that can be maintained in culture, could be a powerful platform to study hematopoiesis and test new therapeutics. It has proven difficult, however, to recreate the complex bone marrow microenvironment needed to support the formation and maintenance of a complete, functional hematopoietic niche in vitro [6][7][8][9] . Although various in vitro culture systems have (Revised NMETH-A19608) been developed to maintain and expand hematopoietic stem and progenitor cells 6-11 , there is currently no method to recreate or study the intact bone marrow microenvironment in vitro. Therefore, studies on hematopoiesis commonly rely on animal models to ensure the presence of an intact bone marrow microenvironment that enables normal physiologic marrow responses [12][13][14][15] . Furthermore, although it has been reported that bone marrow can be engineered in vivo [16][17][18][19] , no method exists to culture engineered bone marrow in vitro. To bridge the functional gap between in vivo and in vitro systems, we developed a method to produce a "bone marrow-on-a-chip" culture system that contains artificial bone and a living marrow, which is first generated in mice, and then explanted whole and maintained in vitro within a microfluidic device. RESULTS In vivo engineering of bone marrowTissue engineering methods have been used to induce formation of new bone with a central marrow compartment in vivo [18][19][20][21] . To explore the possibility of engineering an artificial bone marrow that can be explanted whole, we microfabricated a polydimethylsiloxane (PDMS) device with a central cylindrical cavity (1 mm high x 4 mm diameter) with openings at both ends (Fig. 1a). We filled the hollow compartment with a type I collagen gel containing bone-inducing demineralized bone powder (DBP) and bone morphogenetic proteins (BMP2 and BMP4) [20][21][22] , and implanted it subcutaneously on the back of a mouse (Supplementary Fig. 1). Our goal was to engineer bone that would fill the cylindrical space within the implanted device so that it could be easily removed whole and inserted into a microfluidic system containing a similarly shaped (Revised NMETH-A19608) chamber for in vitro culture (Fig. 1 a,b). These initial studies resulted in the creation of new bone encasing a marrow compartment that formed within the PDMS device 4 to 8 weeks after subcutaneous implantation. Histological analysis revealed that the marrow was largely inhabited by adipocytes and exhibite...

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Section: In Vitro Culture Of Engineered Bone Marrowsupporting

confidence: 71%

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confidence: 99%

Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro

et al. 2014

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“…Moreover, some degree of efficacy has been demonstrated for fibronectin, nanofiber scaffolds (14), and 3D scaffolds (15) in the expansion of HSPCs. However, these attempts could not maintain HSPC properties in the long term.…”

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confidence: 99%

Hematopoiesis in Regenerated Bone Marrow Within Hydroxyapatite Scaffold

et al. 2010

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ABSTRACT:We examined whether regenerated bone marrow (BM) with BM-derived stromal cells (BMSCs) on hydroxyapatite (HA) scaffolds can reconstitute the functional niche. Ly5.2 BMSCs on HA scaffolds were implanted s.c. onto the backs of Ly5.2 recipient mice. Lineage negative Ly5.1 BM cells expressing luciferase (luc) were i.v. administered into the recipient mice. Eight weeks after primary transplantation, secondary implantation was performed; the scaffolds removed from the first recipient mice were s.c. implanted into secondary recipient mice. Lucϩ cells were detected in the scaffolds for 6 mo after secondary implantation. Injection of G-CSF resulted in wide distribution of bioluminescence from the original scaffolds to the whole body. Even after removing the scaffolds from the secondary recipient mice, lucϩ cells were emitted by G-CSF stimulation, indicating that regenerated BM is capable of supporting hematopoietic stem cells (HSCs) and delivering HSCs to native BM in vivo. These data suggest that the functional niche is reconstituted at least partly and that regenerated BM on the scaffold may be used as a portable source of HSCs. (Pediatr Res 68: 35-40, 2010)

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“…We designed our bioengineered implants to mimic the physical and anatomical features of the bone marrow while retaining a high analytic capacity. We used a template-based fabrication method using colloidal crystals to create polyacrylamide hydrogel scaffolds with precise microstructure that resembles decellularized bone (24)(25)(26)(27). The final composition of the scaffold synthesis was a hydrogel that consisted of repeating units of hollowed out "cavities" interconnected by "junctions."…”

Section: Microfabricated Hydrogel Scaffolds Mimic the Anatomy Of Bonementioning

confidence: 99%

Implantable microenvironments to attract hematopoietic stem/cancer cells

Lee

Milwid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The environments that harbor hematopoietic stem and progenitor cells are critical to explore for a better understanding of hematopoiesis during health and disease. These compartments often are inaccessible for controlled and rapid experimentation, thus limiting studies to the evaluation of conventional cell culture and transgenic animal models. Here we describe the manufacture and image-guided monitoring of an engineered microenvironment with user-defined properties that recruits hematopoietic progenitors into the implant. Using intravital imaging and fluorescence molecular tomography, we show in real time that the cell homing and retention process is efficient and durable for short-and longterm engraftment studies. Our results indicate that bone marrow stromal cells, precoated on the implant, accelerate the formation of new sinusoidal blood vessels with vascular integrity at the microcapillary level that enhances the recruitment hematopoietic progenitor cells to the site. This implantable construct can serve as a tool enabling the study of hematopoiesis.

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In vitro analog of human bone marrow from 3D scaffolds with biomimetic inverted colloidal crystal geometry

Cited by 132 publications

References 58 publications

Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro

Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro

Hematopoiesis in Regenerated Bone Marrow Within Hydroxyapatite Scaffold

Implantable microenvironments to attract hematopoietic stem/cancer cells

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