Biology:In vivo bioreactor

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Short description: Tissue engineering paradigm


The in vivo bioreactor is a tissue engineering paradigm that uses bioreactor methodology to grow neotissue in vivo that augments or replaces malfunctioning native tissue. Tissue engineering principles are used to construct a confined, artificial bioreactor space in vivo that hosts a tissue scaffold and key biomolecules necessary for neotissue growth. Said space often requires inoculation with pluripotent or specific stem cells to encourage initial growth, and access to a blood source. A blood source allows for recruitment of stem cells from the body alongside nutrient delivery for continual growth. This delivery of cells and nutrients to the bioreactor eventually results in the formation of a neotissue product.  

Overview

Conceptually, the in vivo bioreactor was borne from complications in a repair method of bone fracture, bone loss, necrosis, and tumor reconstruction known as bone grafting. Traditional bone grafting strategies require fresh, autologous bone harvested from the iliac crest; this harvest site is limited by the amount of bone that can safely be removed, as well as associated pain and morbidity.[1] Other methods include cadaverous allografts and synthetic options (often made of hydroxyapatite) that have become available in recent years. In response to the question of limited bone sourcing, it has been posited that bone can be grown to fit a damaged region within the body through the application of tissue engineering principles.[2]

Tissue engineering is a biomedical engineering discipline that combines biology, chemistry, and engineering to design neotissue (newly formed tissue) on a scaffold.[3] Tissues scaffolds are functionally identical to the extracellular matrix found, acting as a site upon which regenerative cellular components adsorb to encourage cellular growth.[4] This cellular growth is then artificially stimulated by additive growth factors in the environment that encourage tissue formation. The scaffold is often seeded with stem cells and growth additives to encourage a smooth transition from cells to tissues, and more recently, organs. Traditionally, this method of tissue engineering is performed in vitro, where scaffold components and environmental manipulation recreate in vivo stimuli that direct growth. Environmental manipulation includes changes in physical stimulation, pH, potential gradients, cytokine gradients, and oxygen concentration.[5] The overarching goal of in vitro tissue engineering is to create a functional tissue that is equivalent to native tissue in terms of composition, biomechanical properties, and physiological performance.[6] However, in vitro tissue engineering suffers from a limited ability to mimic in vitro conditions, often leading to inadequate tissue substitutes. Therefore, in vivo tissue engineering has been suggested as a method to circumvent the tedium of environmental manipulation and use native in vivo stimuli to direct cell growth. To achieve in vivo tissue growth, an artificial bioreactor space must be established in which cells may grow. The in vivo bioreactor depends on harnessing the reparative qualities of the body to recruit stem cells into an implanted scaffold, and utilize vasculature to supply all necessary growth components.

Design

Cells

Tissue engineering done in vivo is capable of recruiting local cellular populations into a bioreactor space.[2][7] Indeed a range of neotissue growth has been shown: bone, cartilage, fat, and muscle.[7][8][9][10] In theory, any tissue type could be grown in this manner if all necessary components (growth factors, environmental and physical ques) are met. Recruitment of stem cells require a complex process of mobilization from their niche,[11] though research suggests that mature cells transplanted upon the bioreactor scaffold can improve stem cell recruitment.[12][13][14] These cells secrete growth factors that promote repair and can be co-cultured with stem cells to improve tissue formation.

Scaffolds

Scaffold materials are designed to enhance tissue formation through control of the local and surrounding environments.[15][16][17] Scaffolds are critical in regulating cellular growth and provide a volume in which vascularization and stem cell differentiation can occur.[18] Scaffold geometry significantly affects tissue differentiation through physical growth ques. Predicting tissue formation computationally requires theories that link physical growth ques to cell differentiation. Current models rely on mechano-regulation theory, widely shaped by Prendergast et al. for predicting cell growth.[19] Thus a quantitative analysis of geometry and materials commonly used in tissue scaffolds is capable.

Such materials include:

Bioreactors

Methods

Initially, focusing on bone growth, subcutaneous pockets were used for bone prefabrication as a simple in vivo bioreactor model. The pocket is an artificially created space between varying levels of subcutaneous fascia. The location provides regenerative ques to the bioreactor implant but does not rely on pre-existing bone tissue as a substrate. Furthermore, these bioreactors may be wrapped with muscle tissue to encourage vascularization and bone growth. Another strategy is through the use of a periosteal flap wrapped around the bioreactor, or the scaffold itself to create an in vivo bioreactor. This strategy utilizes the guided bone regeneration treatment scheme, and is a safe method for bone prefabrication. These ‘flap’ methods of packing the bioreactor within fascia, or wrapping it in tissue is effective, though somewhat random due to the non-directed vascularization these methods incur. The axial vascular bundle (AVB) strategy requires that an artery and vein are inserted in an in vitro bioreactor to transport growth factors, cells, and remove waste. This ultimately results in extensive vascularization of the bioreactor space and a vast improvement in growth capability. This vascularization, though effective, is limited by the surface contact that it can achieve between the scaffold and the capillaries filling the bioreactor space. Thus, a combination of the flap and AVB techniques can maximize the growth rate and vascular contact of the bioreactor as suggested by Han and Dai, by inserting a vascular bundle into a scaffold wrapped in either musculature or periosteum.[28] If inadequate pre-existing vasculature is present in the growth site due to damage or disease, an arteriovenous loop (AVL) can be used. The AVL strategy requires a surgical connection be made between an artery of vein to form an arteriovenous fistula which is then placed within an in vitro bioreactor space containing a scaffold. A capillary network will form from this loop and accelerate the vascularization of new tissue.[29]

Materials

Materials used in the construction of an in vivo bioreactor space vary widely depending on the type of substrate, type of tissue, and mechanical demands of said tissue being grown. At its simplest, a bioreactor space will be created between tissue layers through the use of hydrogel injections to create a bioreactor space. Early models used an impermeable silicone shroud to encase a scaffold,[6] though more recent studies have begun 3D printing custom bioreactor molds to further enhance the mechanical growth properties of the bioreactors. The choice of bioreactor chamber material generally requires that it is nontoxic and medical grade, examples include: “silicon, polycarbonate, and acrylic polymer”.[27] Recently both Teflon and titanium have been used in the growth of bone.[27] One study utilized Polymethyl methacrylate as a chamber material and 3D printed hollow rectangular blocks.[30] Yet another study pushed the limits of the in vivo bioreactor by proving that the omentum is suitable as a bioreactor space and chamber. Specifically, highly vascularized and functional bladder tissue was grown within the omentum space.[31]

Examples

An example of the implementation of the IVB approach was in the engineering of autologous bone by injecting calcium alginate in a sub-periosteal location.[32][33] The periosteum is a membrane that covers the long bones, jawbone, ribs and the skull. This membrane contains an endogenous population of pluripotent cells called the periosteal cells, which are a type of mesenchymal stem cells (MSC), which reside in the cambium layer, i.e., the side facing the bone. A key step in the procedure is the elevation of the periosteum without damaging the cambium surface and to ensure this a new technique called hydraulic elevation was developed.[34]

The choice of the sub-periosteum site is used because stimulation of the cambium layer using transforming growth factor–beta resulted in enhanced chondrogenesis, i.e., formation of cartilage. In development the formation of bone can either occur via a Cartilage template initially formed by the MSCs that then gets ossified through a process called endochondral ossification or directly from MSC differentiation to bone via a process termed intra-membranous ossification. Upon exposure of the periosteal cells to calcium from the alginate gel, these cells become bone cells and start producing bone matrix through the intra-membranous ossification process, recapitulating all steps of bone matrix deposition. The extension of the IVB paradigm to engineering autologous hyaline cartilage was also recently demonstrated.[35] In this case, agarose is injected and this triggers local hypoxia, which then results in the differentiation of the periosteal MSCs into articular chondrocytes, i.e. cells similar to those found in the joint cartilage. Since this processes occurs in a relative short period of less than two weeks and cartilage can remodel into bone, this approach might provide some advantages in treatment of both cartilage and bone loss. The IVB concept needs to be however realized in humans and this is currently being undertaken.

See also

Further reading

References

  1. ↑ Dusseldorp, Joseph Richard; Mobbs, Ralph J. (September 2009). "Iliac crest reconstruction to reduce donor-site morbidity: technical note" (in en). European Spine Journal 18 (9): 1386–90. doi:10.1007/s00586-009-1108-4. PMID 19653014. 
  2. ↑ 2.0 2.1 Sladkova, Martina; de Peppo, Giuseppe (2014-06-11). "Bioreactor Systems for Human Bone Tissue Engineering" (in en). Processes 2 (2): 494–525. doi:10.3390/pr2020494. ISSN 2227-9717. 
  3. ↑ Ikada, Yoshito (2006-10-22). "Challenges in tissue engineering" (in en). Journal of the Royal Society Interface 3 (10): 589–601. doi:10.1098/rsif.2006.0124. PMID 16971328. 
  4. ↑ Oragui, Emeka; Nannaparaju, Madhusudhan; Khan, Wasim S. (2011). "Suppl 2: The Role of Bioreactors in Tissue Engineering for Musculoskeletal Applications" (in en). The Open Orthopaedics Journal 5: 267–70. doi:10.2174/1874325001105010267. PMID 21886691. 
  5. ↑ Badylak, Stephen F.; Nerem, Robert M. (2010-02-23). "Progress in tissue engineering and regenerative medicine". Proceedings of the National Academy of Sciences 107 (8): 3285–3286. doi:10.1073/pnas.1000256107. ISSN 0027-8424. PMID 20181571. 
  6. ↑ 6.0 6.1 Holt, Ginger E.; Halpern, Jennifer L.; Dovan, Thomas T.; Hamming, David; Schwartz, Herbert S. (2005). "Evolution of an in vivo bioreactor" (in en). Journal of Orthopaedic Research 23 (4): 916–923. doi:10.1016/j.orthres.2004.10.005. ISSN 1554-527X. PMID 16023008. 
  7. ↑ 7.0 7.1 Stevens, M. M.; Marini, R. P.; Schaefer, D.; Aronson, J.; Langer, R.; Shastri, V. P. (2005-07-29). "In vivo engineering of organs: The bone bioreactor". Proceedings of the National Academy of Sciences 102 (32): 11450–11455. doi:10.1073/pnas.0504705102. ISSN 0027-8424. PMID 16055556. Bibcode: 2005PNAS..10211450S. 
  8. ↑ Moya, Monica L.; Cheng, Ming-Huei; Huang, Jung-Ju; Francis-Sedlak, Megan E.; Kao, Shu-wei; Opara, Emmanuel C.; Brey, Eric M. (April 2010). "The effect of FGF-1 loaded alginate microbeads on neovascularization and adipogenesis in a vascular pedicle model of adipose tissue engineering". Biomaterials 31 (10): 2816–2826. doi:10.1016/j.biomaterials.2009.12.053. ISSN 0142-9612. PMID 20080298. 
  9. ↑ Scime, Anthony (2009). "Advances in myogenic cell transplantation and skeletal muscle tissue engineering". Frontiers in Bioscience 14 (14): 3012–23. doi:10.2741/3431. ISSN 1093-9946. PMID 19273253. 
  10. ↑ Stillaert, F.B.; Di Bartolo, C.; Hunt, J.A.; Rhodes, N.P.; Tognana, E.; Monstrey, S.; Blondeel, P.N. (October 2008). "Human clinical experience with adipose precursor cells seeded on hyaluronic acid-based spongy scaffolds". Biomaterials 29 (29): 3953–3959. doi:10.1016/j.biomaterials.2008.06.005. ISSN 0142-9612. PMID 18635258. http://dx.doi.org/10.1016/j.biomaterials.2008.06.005. 
  11. ↑ 11.0 11.1 McCullen, Seth D; Chow, Andre GY; Stevens, Molly M (2011-10-01). "In vivo tissue engineering of musculoskeletal tissues" (in en). Current Opinion in Biotechnology. Tissue, cell and pathway engineering 22 (5): 715–720. doi:10.1016/j.copbio.2011.05.001. ISSN 0958-1669. PMID 21646011. http://www.sciencedirect.com/science/article/pii/S0958166911000887. 
  12. ↑ Fong, Eliza L.S.; Chan, Casey K.; Goodman, Stuart B. (January 2011). "Stem cell homing in musculoskeletal injury". Biomaterials 32 (2): 395–409. doi:10.1016/j.biomaterials.2010.08.101. ISSN 0142-9612. PMID 20933277. 
  13. ↑ da Silva Meirelles, Lindolfo; Caplan, Arnold I.; Nardi, Nance Beyer (September 2008). "In Search of the In Vivo Identity of Mesenchymal Stem Cells". Stem Cells 26 (9): 2287–2299. doi:10.1634/stemcells.2007-1122. ISSN 1066-5099. PMID 18566331. 
  14. ↑ Chen, Liwen; Tredget, Edward E.; Wu, Philip Y. G.; Wu, Yaojiong (2008-04-02). "Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing". PLOS ONE 3 (4): e1886. doi:10.1371/journal.pone.0001886. ISSN 1932-6203. PMID 18382669. Bibcode: 2008PLoSO...3.1886C. 
  15. ↑ Shastri, V. Prasad (2009-11-06). "In vivo Engineering of Tissues: Biological Considerations, Challenges, Strategies, and Future Directions". Advanced Materials 21 (41): 3246–54. doi:10.1002/adma.200990155. ISSN 0935-9648. PMID 20882495. 
  16. ↑ Place, Elsie S.; Evans, Nicholas D.; Stevens, Molly M. (June 2009). "Complexity in biomaterials for tissue engineering". Nature Materials 8 (6): 457–470. doi:10.1038/nmat2441. ISSN 1476-1122. PMID 19458646. Bibcode: 2009NatMa...8..457P. http://dx.doi.org/10.1038/nmat2441. 
  17. ↑ Zhu, Junmin (June 2010). "Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering". Biomaterials 31 (17): 4639–4656. doi:10.1016/j.biomaterials.2010.02.044. ISSN 0142-9612. PMID 20303169. 
  18. ↑ MUSCHLER, GEORGE F.; NAKAMOTO, CHIZU; GRIFFITH, LINDA G. (July 2004). "Engineering Principles of Clinical Cell-Based Tissue Engineering". The Journal of Bone and Joint Surgery, American Volume 86 (7): 1541–1558. doi:10.2106/00004623-200407000-00029. ISSN 0021-9355. PMID 15252108. http://dx.doi.org/10.2106/00004623-200407000-00029. 
  19. ↑ Prendergast, P.J.; Huiskes, R.; Søballe, K. (June 1997). "Biophysical stimuli on cells during tissue differentiation at implant interfaces". Journal of Biomechanics 30 (6): 539–548. doi:10.1016/s0021-9290(96)00140-6. ISSN 0021-9290. PMID 9165386. http://dx.doi.org/10.1016/s0021-9290(96)00140-6. 
  20. ↑ 20.0 20.1 Oragui, Emeka; Nannaparaju, Madhusudhan; Khan, Wasim S (2011-07-28). "The Role of Bioreactors in Tissue Engineering for Musculoskeletal Applications". The Open Orthopaedics Journal 5: 267–270. doi:10.2174/1874325001105010267. ISSN 1874-3250. PMID 21886691. 
  21. ↑ Thevenot, Paul T.; Nair, Ashwin M.; Shen, Jinhui; Lotfi, Parisa; Ko, Cheng-Yu; Tang, Liping (May 2010). "The effect of incorporation of SDF-1α into PLGA scaffolds on stem cell recruitment and the inflammatory response". Biomaterials 31 (14): 3997–4008. doi:10.1016/j.biomaterials.2010.01.144. ISSN 0142-9612. PMID 20185171. 
  22. ↑ Shen, Weiliang; Chen, Xiao; Chen, Jialin; Yin, Zi; Heng, Boon Chin; Chen, Weishan; Ouyang, Hong-Wei (October 2010). "The effect of incorporation of exogenous stromal cell-derived factor-1 alpha within a knitted silk-collagen sponge scaffold on tendon regeneration". Biomaterials 31 (28): 7239–7249. doi:10.1016/j.biomaterials.2010.05.040. ISSN 0142-9612. PMID 20615544. http://dx.doi.org/10.1016/j.biomaterials.2010.05.040. 
  23. ↑ BADYLAK, S; FREYTES, D; GILBERT, T (January 2009). "Extracellular matrix as a biological scaffold material: Structure and function". Acta Biomaterialia 5 (1): 1–13. doi:10.1016/j.actbio.2008.09.013. ISSN 1742-7061. PMID 18938117. http://dx.doi.org/10.1016/j.actbio.2008.09.013. 
  24. ↑ Zhang, Shuming; Greenfield, Megan A.; Mata, Alvaro; Palmer, Liam C.; Bitton, Ronit; Mantei, Jason R.; Aparicio, Conrado; de la Cruz, Monica Olvera et al. (2010-06-13). "A self-assembly pathway to aligned monodomain gels". Nature Materials 9 (7): 594–601. doi:10.1038/nmat2778. ISSN 1476-1122. PMID 20543836. Bibcode: 2010NatMa...9..594Z. 
  25. ↑ Supramolecular GAG-like Self-Assembled Glycopeptide Nanofibers Induce Chondrogenesis and Cartilage Regeneration. doi:10.1021/acs.biomac.5b01669.s001. 
  26. ↑ "PB33 Autologous in vitro cartilage. Engineering, characterization, application". Osteoarthritis and Cartilage 9: S53–S54. September 2001. doi:10.1016/s1063-4584(01)80358-7. ISSN 1063-4584. 
  27. ↑ 27.0 27.1 27.2 27.3 Yap, Kiryu K.; Yeoh, George C.; Morrison, Wayne A.; Mitchell, Geraldine M. (2018-10-01). "The Vascularised Chamber as an In Vivo Bioreactor" (in en). Trends in Biotechnology 36 (10): 1011–1024. doi:10.1016/j.tibtech.2018.05.009. ISSN 0167-7799. PMID 29937050. http://www.sciencedirect.com/science/article/pii/S0167779918301446. 
  28. ↑ Zhang, Haifeng; Mao, Xiyuan; Zhao, Danyang; Jiang, Wenbo; Du, Zijing; Li, Qingfeng; Jiang, Chaohua; Han, Dong (2017-11-10). "Three dimensional printed polylactic acid-hydroxyapatite composite scaffolds for prefabricating vascularized tissue engineered bone: An in vivo bioreactor model" (in en). Scientific Reports 7 (1): 15255. doi:10.1038/s41598-017-14923-7. ISSN 2045-2322. PMID 29127293. Bibcode: 2017NatSR...715255Z. 
  29. ↑ Lokmic, Zerina; Stillaert, Filip; Morrison, Wayne A.; Thompson, Erik W.; Mitchell, Geraldine M. (February 2007). "An arteriovenous loop in a protected space generates a permanent, highly vascular, tissue-engineered construct". FASEB Journal 21 (2): 511–522. doi:10.1096/fj.06-6614com. ISSN 1530-6860. PMID 17172640. https://pubmed.ncbi.nlm.nih.gov/17172640/. 
  30. ↑ Tatara, Alexander M.; Koons, Gerry L.; Watson, Emma; Piepergerdes, Trenton C.; Shah, Sarita R.; Smith, Brandon T.; Shum, Jonathan; Melville, James C. et al. (2019-04-02). "Biomaterials-aided mandibular reconstruction using in vivo bioreactors" (in en). Proceedings of the National Academy of Sciences 116 (14): 6954–6963. doi:10.1073/pnas.1819246116. ISSN 0027-8424. PMID 30886100. Bibcode: 2019PNAS..116.6954T. 
  31. ↑ Baumert, Hervé; Simon, Pascal; Hekmati, Mehrak; Fromont, Gaëlle; Levy, Maryline; Balaton, André; Molinié, Vincent; Malavaud, Bernard (2007-09-01). "Development of a Seeded Scaffold in the Great Omentum: Feasibility of an in vivo Bioreactor for Bladder Tissue Engineering" (in en). European Urology 52 (3): 884–892. doi:10.1016/j.eururo.2006.11.044. ISSN 0302-2838. PMID 17229515. http://www.sciencedirect.com/science/article/pii/S0302283806014485. 
  32. ↑ Stevens, Molly M.; Marini, Robert P.; Schaefer, Dirk; Aronson, Joshua; Langer, Robert; Shastri, V. Prasad (June 8, 2005). "In vivo engineering of organs: The bone bioreactor". Proceedings of the National Academy of Sciences, USA 102 (32): 11450–11455. doi:10.1073/pnas.0504705102. PMID 16055556. Bibcode: 2005PNAS..10211450S. 
  33. ↑ Service, Robert F. (29 July 2005). "Technique Uses Body as 'Bioreactor' to Grow New Bone". Science 309 (5735): 683. doi:10.1126/science.309.5735.683a. PMID 16051759. 
  34. ↑ Marini, Robert P.; Stevens, Molly M.; Langer, Robert; Shastri, V. Prasad (2004). "Hydraulic Elevation of the Periosteum: A Novel Technique for Periosteal Harvest". Journal of Investigative Surgery 17 (4): 229–233. doi:10.1080/08941930490472073. PMID 15371165. 
  35. ↑ Emans, Pieter J.; Lodewijk W. van Rhijn; Welting, Tim J. M.; Cremers, Andy; Wijnands, Nina; Spaapen, Frank; J. Voncken, Willem; Shastri, V. Prasad (January 7, 2010). "Autologous engineering of cartilage". Proceedings of the National Academy of Sciences, USA 107 (8): 3418–3423. doi:10.1073/pnas.0907774107. PMID 20133690. Bibcode: 2010PNAS..107.3418E. 



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