State of the art and future perspectives for biomaterials design for regenerative medicine

In this contribution, Roberto Portillo-Lara & Nasim Annabi comment on future perspectives of rational design for efficient clinical translation of biomaterials for regenerative medicine.

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Apr 10, 2017
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Roberto Portillo-Lara1,2 & Nasim Annabi1,3

1Department of Chemical Engineering, Northeastern University (Boston, USA)

2Centro de Biotecnología-FEMSA, Tecnológico de Monterrey (Monterrey, México)

3Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, (MA, USA)

Regenerative medicine aims to replace the partial or complete, physical and/or functional loss of a given tissue caused by disease, trauma, or congenital defects [1]. This multidisciplinary field comprises various strategies based on the combination of different types of biomaterials, cells and physicochemical factors, to replace the structure and function of a tissue or promote tissue healing [2, 3].

One of the key challenges in regenerative medicine is the engineering of three-dimensional (3D) microenvironments that can recapitulate the complex features of physiological tissues. In this context, biomaterials are often used in regenerative medicine because they can mimic the native extracellular matrix (ECM) and provide structural support to the engineered tissue constructs [4].

The ECM is a type of naturally occurring mixed biopolymer that is secreted by cells in physiological tissues and possesses a unique and tissue-specific architecture and composition [5]. Apart from its role in structural support, the ECM exerts numerous roles through bioactive motifs that function as cell-binding sites, cell differentiation cues and modulators of intracellular signaling pathways [6]. In addition, physiological microenvironments exist in a continuous state of dynamic reciprocity, which is manifested by spatiotemporal changes in the composition of the ECM [7]. Therefore, significant efforts have been made towards the engineering of synthetic-based and naturally derived biomaterials that mimic the complex features of ECM for experimental and clinical applications [8-10].

Engineering biomimetic tissue constructs could be carried out either through in vitro culture and then implant or in vivo development [11]. To generate functional tissue constructs in vitro, biomaterials are used as scaffolds for cell attachment and growth in the presence of physicochemical factors that stimulate new tissue formation, which can be then implanted into organism.

Alternatively, a combination of biomaterials, cells and biological factors can be delivered in vivo to promote local autologous tissue growth. Moreover, as biomaterials chemistries become increasingly more sophisticated, their ability to direct tissue morphogenesis and repair in vivo, without the need for exogenous cultured cells has also increased [12].

This paradigm shift in biomaterial development, from passive structures to bioactive modulators of cell fate will have significant regulatory implications, as biomaterials gain biological relevance and start to exhibit drug-like mechanisms of action [13]. Furthermore, the design of new biomaterials should take into consideration the crosstalk that occurs between different cell types in vivo during tissue regeneration and repair, such as autocrine and paracrine signaling, cell migration and recruitment, as well as the paramount role of the immune component of the microenvironment [14].

The experimental design and clinical translation of biomaterials comprises various stages related to the conception of the material formulation, followed by in vitro physical and biological characterization, and in vivo evaluation of biocompatibility and bioactivity using different animal models. In recent years, new in vitro and in vivo techniques for high-throughput screening of complex biological outputs are being developed, to better analyze biological responses to biomaterials and increase the efficiency of clinical translation [15, 16]. Furthermore, preclinical and clinical evaluation provides valuable insight into the design parameters that are determinant for therapeutic efficacy, which can be then incorporated into new approaches to improve future product development.

The successful clinical translation of future biomaterials-based strategies in regenerative medicine will require: (i) effectively recapitulating organ and tissue level architecture; (ii) promoting vascularization and innervation to improve host graft integration; and (iii) modulation of the microenvironment to induce therapeutic responses [17]. Conventional strategies to recapitulate physiological architectures include the use of decellularized tissues [18], polymeric scaffolds [19], or cell sheets [20].

More recently, 3D bioprinting techniques have been used to engineer structures with precise control over the arrangement of biomaterials and cells within the engineered biomimetic tissue constructs [21, 22]. In addition, the efficient implementation of engineered biomimetic tissues requires adequate grafting and integration with the host. In the case of cell-laden implants, proper integration with the vasculature is critical to ensure implant survival and success. Strategies to induce implant vascularization include the controlled release of angiogenic factors, as well as the in vitro or in vivo pre-vascularization of the graft [23, 24].

Another important aspect for tissue integration where motor control (e.g. muscle tissue) or sensation (e.g. epidermis) is important for proper tissue function is the innervation of the implant [25]. Innervation of engineered tissue constructs may be induced by angiogenic or nerve growth factors, as well as through micropatterning of hydrogels that could guide nerve growth upon implantation [26-28].

Lastly, as current understanding of the role of cytokines and growth factors, as well as their interactions with cells and the ECM increases, novel biomaterials are being developed to better mimic the physiological regenerative microenvironment [29, 30]. For instance, the transplantation of immunomodulatory biomaterials could be used to control local immune microenvironment, reduce inflammatory responses and improve the overall therapeutic efficacy [31, 32].

The implementation of advanced biomaterials in regenerative tissue engineering has led to significant advancements in the last decades[14]. As scientific research has increased the understanding of cellular responses to biochemical and biophysical stimuli, these fundamental biological processes are now being engineered into smart and multi-functional biomaterials with enhanced bioactivity.

Sophisticated chemistries now allow the mimicking of the architecture and physicochemical cues of regenerative microenvironments. However, as experimental platforms become increasingly more complex, it is important not to neglect or impede the innate physiological processes that modulate tissue regeneration and repair. In fact, accumulating evidence suggests that the immune system functions not only as a regulator of material biocompatibility but is also key for tissue regeneration, a process known as biomaterials directed regenerative immunology [33, 34].

Experimental approaches in the fields of biomaterials and regenerative medicine will mature from iterative approaches to evidence-based strategies, incorporating new knowledge obtained from preclinical and clinical studies. Therefore, the design of novel biomaterials may shift from increasingly complex chemistries to simplistic, smart and multi-functional patient-specific approaches that are cost-effective and exhibit higher therapeutic efficacy.


N.A. and R.P.L. acknowledge the support from the Department of Chemical Engineering and College of Engineering at Northeastern University. R.P.L. acknowledges the support from the School of Sciences and Engineering at Tecnológico de Monterrey.

Financial & competing interests disclosure

The authors declare no financial and competing interests.


  1. National Academies of Sciences, E. and H. Medicine, Medicine, Division, Board on Health Sciences, Policy Forum on Regenerative, Medicine, The National Academies Collection: Reports funded by National Institutes of Health, in Exploring the State of the Science in the Field of Regenerative Medicine: Challenges of and Opportunities for Cellular Therapies: Proceedings of a Workshop. 2017, National Academies Press (US), National Academy of Sciences.
  2. Mikos AG et al. Engineering complex tissues. Tissue Eng. 12(12): p 3307-39 (2006)
  3. Bajaj P et al. 3D biofabrication strategies for tissue engineering and regenerative medicine. Annu Rev Biomed Eng. 16: p 247-76 (2014)
  4. Huebsch N, Mooney DJ. Inspiration and application in the evolution of biomaterials. Nature. 462(7272): p 426-32 (2009)
  5. Ma PX. Biomaterials and regenerative medicine. 2014, Cambridge, United Kingdom: Cambridge University Press. xvi, 703 pages.
  6. Kosuge D et al. Biomaterials and scaffolds in bone and musculoskeletal engineering. Curr Stem Cell Res Ther. 8(3): p 185-91 (2013)
  7. Brown BN, Badylak SF. Extracellular matrix as an inductive scaffold for functional tissue reconstruction. Transl Res. 163(4): p. 268-85 (2014)
  8. Bedian L et al. Bio-based materials with novel characteristics for tissue engineering applications - A review. Int J Biol Macromol. 98: p 837-846 (2017)
  9. Zhou J et al. Supramolecular biofunctional materials. Biomaterials. 129: p 1-27 (2017)
  10. Guan X et al. Development of hydrogels for regenerative engineering. Biotechnol J (2017)
  11. Pashuck ET, Stevens MM. Designing regenerative biomaterial therapies for the clinic. Sci Transl Med. 4(160): p 160sr4 (2012)
  12. Lutolf MP, Hubbell JA. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol. 23(1): p 47-55 (2005)
  13. Regulatory affairs for biomaterials and medical devices. Woodhead publishing series in biomaterials. 2014, Philadelphia, PA: Woodhead Pub. pages cm.
  14. Sadtler K et al. Design, clinical translation and immunological response of biomaterials in regenerative medicine. Nature Reviews Materials. 1: p 16040 (2016)
  15. Beachley VZ et al. Tissue matrix arrays for high-throughput screening and systems analysis of cell function. Nat Methods. 12(12): p 1197-204 (2015)
  16. Vegas AJ et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol. 34(3): p 345-52 (2016)
  17. Mao AS, Mooney DJ. Regenerative medicine: Current therapies and future directions. Proc Natl Acad Sci U S A. 112(47): p 14452-9 (2015)
  18. Seetapun D, Ross JJ. Eliminating the organ transplant waiting list: The future with perfusion decellularized organs. Surgery (2016).
  19. Yang S et al. The design of scaffolds for use in tissue engineering. Part I. Traditional factors. Tissue Eng. 7(6): p 679-89 (2001)
  20. Masumoto H, Yamashita JK. Human iPS Cell-Derived Cardiac Tissue Sheets: a Platform for Cardiac Regeneration. Curr Treat Options Cardiovasc Med. 18(11): p 65 (2016)
  21. Ozbolat IT. Bioprinting scale-up tissue and organ constructs for transplantation. Trends Biotechnol. 33(7): p 395-400 (2015)
  22. Hong N et al. 3D bioprinting and its in vivo applications. J Biomed Mater Res B Appl Biomater (2017)
  23. Datta P, Ayan B, Ozbolat IT. Bioprinting for vascular and vascularized tissue biofabrication. Acta Biomater. 51: p 1-20 (2017)
  24. Laschke MW, Menger MD. Prevascularization in tissue engineering: Current concepts and future directions. Biotechnol Adv. 34(2): p 112-21 (2016)
  25. Guo X et al. Tissue engineering the mechanosensory circuit of the stretch reflex arc with human stem cells: Sensory neuron innervation of intrafusal muscle fibers. Biomaterials. 122: p 179-187 (2017)
  26. da Silva LP et al. Stem Cell-Laden Hyaluronic Acid-Based Spongy-Like Hydrogels for an Integrated Healing of Diabetic Wounds Pathophysiologies. J Invest Dermatol (2017)
  27. Gurlin RE et al. Vascularization and innervation of slits within polydimethylsiloxane sheets in the subcutaneous space of athymic nude mice. J Tissue Eng. 8: p 2041731417691645 (2017).
  28. Tsai EC et al. Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials. 27(3): p 519-33 (2006)
  29. Rice JJ et al. Engineering the regenerative microenvironment with biomaterials. Adv Healthc Mater. 2(1): p 57-71 (2013)
  30. Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 20(8): p 857-69 (2014)
  31. Rammal H, et al. Bio-Inspired Nano-Featured Substrates: Suitable Environment for Bone Regeneration. ACS Appl Mater Interfaces (2017)
  32. Cheng B et al. Harnessing the early post-injury inflammatory responses for cardiac regeneration. J Biomed Sci. 24(1): p 7 (2017)
  33. Vrana NE. Immunomodulatory biomaterials and regenerative immunology. Future Sci OA. 2(4): p FSO146 (2016)
  34. Vishwakarma A et al. Engineering Immunomodulatory Biomaterials To Tune the Inflammatory Response. Trends Biotechnol. 34(6): p 470-82 (2016)
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