Bioadaptability of biomaterials: Aiming at precision medicine

Bioadaptability, proposed earlier to accentuate the biomaterial-host interactivity, incites the development of adaptable biomaterials. Esser-Kahn et al.3Wang Z. Wang J. Ayarza J. Steeves T. Hu Z. Manna S. Esser-Kahn A.P. Bio-inspired mechanically adaptive materials through vibration-induced crosslinking.Nat. Mater. 2021; 20: 869-874Crossref PubMed Scopus (23) Google Scholar recently reported a biomaterial that can self-adapt to its mechanical environment as potential bone implants. Such endeavors allow “precise bioadaptability” for fueling precision medicine. Bioadaptability, proposed earlier to accentuate the biomaterial-host interactivity, incites the development of adaptable biomaterials. Esser-Kahn et al.3Wang Z. Wang J. Ayarza J. Steeves T. Hu Z. Manna S. Esser-Kahn A.P. Bio-inspired mechanically adaptive materials through vibration-induced crosslinking.Nat. Mater. 2021; 20: 869-874Crossref PubMed Scopus (23) Google Scholar recently reported a biomaterial that can self-adapt to its mechanical environment as potential bone implants. Such endeavors allow “precise bioadaptability” for fueling precision medicine. Spurred on by innovative materials chemistry and enabling engineering tactics, alongside a deeper and expanded understanding of biology and life, biomaterials with designer compositions, elaborate structures, and unprecedented properties have emerged over the last decade. These have been increasingly synthesized and adopted to improve the outcomes of tissue engineering. Accordingly, a demanding benchmark, bioadaptability, was earlier coined to more systematically evaluate the suitability of a material for bioapplications.1Wang Y. Bioadaptability: An Innovative Concept for Biomaterials.J. Mater. Sci. Technol. 2016; 32: 801-809Crossref Scopus (39) Google Scholar Bioadaptability heralds a new age in biomaterials science, where the paradigm shift from biocompatibility and bioactivity to bioresponsiveness and automation for the selection, design, and assessment of biomedical materials is occurring. Over the past few years, there has been a growing realization that bioadaptability, in essence, is a spatiotemporally specific tenet that hinges largely on the precise and dynamic interactivity between biomaterials and hosts. Here, we further conceive “precise bioadaptability,” which encompasses five key components—biology, mechanics, chemistry, surface, and geometry—to enable precision regenerative medicine (Figure 1). In contrast to biocompatibility that focuses primarily on static or overall performances, precise bioadaptability underscores the capability of a biomaterial to dynamically and actively respond to either endogenous biological milieus/signals or externally applied triggers with both spatial and temporal precision. When interfaced with the human body, such a material would, in an ideally synergistic manner, interplay with biological microenvironments and participate in physiological processes. Here, spatiotemporally orchestrated events would occur at scales ranging from atomic, molecular, and cellular regimes to tissue, organ, and system levels and within time frames spanning from seconds to months and years. Furthermore, exogenous stimuli—for example, photo-fluorescence, X-rays, mechanical force, ultrasound, magnetics, or electrochemical potential—could be applied to endow or augment the bioadaptability of materials by enabling responses to the stimuli. Moreover, real-time monitoring and regulation of the dynamic bioadaptive processes of biomaterials via in situ bioimaging or biosensing will enable feedback-responsive theranostics and regeneration. The development of biomaterials fulfilling these criteria underlies precision medicine. Biomaterials’ capability to create, in situ, host-harmonized tissue microenvironments lies at the heart of precise bioadaptability.1Wang Y. Bioadaptability: An Innovative Concept for Biomaterials.J. Mater. Sci. Technol. 2016; 32: 801-809Crossref Scopus (39) Google Scholar In this light, adaptable biomaterials should strive to capture and reproduce the (bio)physical and (bio)chemical cues inherent to the tissue to be repaired, thus eliciting beneficial immunoregulatory and regenerative responses. For example, calcium phosphates and other bioceramics are advantageous for bone repair as they produce ionic components akin to those of natural bone. In addition, fibrous biomaterials that resemble native extracellular matrices have found widespread use in tissue engineering. Desirably, a precisely adaptable biomaterial ought to recapitulate the targeted tissue with spatiotemporal precision and hierarchical accuracy, ranging from atoms and molecules (genes, proteins, etc.) to cells (including organelles) and to tissues and organs. In addition, it is also useful to engineer bioadaptability to the developmental biology of the regenerated tissues. For example, development-mimetic strategies, such as endochondral ossification, provide a new window for developing large vascularized bone. For another example, there is growing interest in the synergistic regeneration of bone and associated vasculature, nerves, and adjoining soft tissues (cartilage, tendon, ligaments, and muscles).2Calejo I. Costa-Almeida R. Reis R.L. Gomes M.E. A Physiology-Inspired Multifactorial Toolbox in Soft-to-Hard Musculoskeletal Interface Tissue Engineering.Trends Biotechnol. 2020; 38: 83-98Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Such biology-centered rationales should be well adhered to when designing adaptable biomaterials for the precision regeneration of tissues/organs. Mechanics constitutes another integral aspect of bioadaptability. Different cells, tissues, and organs have distinct mechanical properties (notably stiffness) corresponding to varied biological functionality. In particular, cells are capable of sensing matrix or substrate elasticity and can transduce the perceived mechanical signals into cascade physiological responses, e.g., from adhesion to differentiation. Biomechanical properties are time and dimension adaptable; therefore, it would be nontrivial to integrate mechano-adaptable biomaterials with dynamically and progressively matched mechanical properties into native living systems (ideally at nano/micro-to-macro scales). As a prime highlight of this Preview, the Esser-Kahn group recently formulated a novel composite material that can identify and adapt to the mechanical environment experienced, aiming to recapitulate bone’s ability of self-adapting to body loads and developing anisotropic moduli. This composite is capable of varying its modulus as a function of force, time, and frequency of external mechanical agitation.3Wang Z. Wang J. Ayarza J. Steeves T. Hu Z. Manna S. Esser-Kahn A.P. Bio-inspired mechanically adaptive materials through vibration-induced crosslinking.Nat. Mater. 2021; 20: 869-874Crossref PubMed Scopus (23) Google Scholar The organo-gel composite consists of a methyl cellulose matrix, dynamically reactive materials (thiol-ene “click components”), and a piezoelectric sensor (ZnO particles). Upon vibration, the ZnO particles transduce mechanical energy to provoke a thiol-ene click reaction to crosslink the polymer, thus inducing adaptive strengthening. By repetitive mechanochemical activation, the polymer composite gel can be made 66 times stronger. Such stress-induced adaptive behavior is reminiscent of bone remodeling, hinting at the material’s great potential in bone replacement. Similarly, a self-stiffening material system inspired by the mineralization process of bone was developed by Kang’s group.4Orrego S. Chen Z. Krekora U. Hou D. Jeon S.-Y. Pittman M. Montoya C. Chen Y. Kang S.H. Bioinspired Materials with Self-Adaptable Mechanical Properties.Adv. Mater. 2020; 32: e1906970Crossref PubMed Scopus (19) Google Scholar The authors fabricated piezoelectric polymer scaffolds that are capable of self-regulating their surface electric charges in response to external mechanical loading. By soaking in a simulated body fluid, the amount of minerals deposited on the porous scaffold could be tailored proportionally to the magnitude of stress subjected to, while simultaneously allowing spatial precision in mineralization. This modulates mineral buildup on the surface of the polymer scaffold, which enables the self-adapting mechanical property. Such technology opens enticing possibilities of smart self-healable bone implants and shape-shifting 4D materials for load-bearing applications. Other research aims at developing adaptive softening of mechanically stiff materials, which is an enabler for development of dampening systems, soft robotics, and smart implants for tissue growth. An example of this is the work of Jiao et al., where joule heating was used to reversibly switch the mechanical properties of cellulose nanofibrils/polymer nanopaper materials from stiff to soft via on/off cycles of electricity.5Jiao D. Lossada F. Guo J. Skarsetz O. Hoenders D. Liu J. Walther A. Electrical switching of high-performance bioinspired nanocellulose nanocomposites.Nat. Commun. 2021; 12: 1312Crossref PubMed Scopus (15) Google Scholar Biodegradation is a principal route toward chemical bioadaptability, especially when implantable biomaterials are concerned. Biodegradable materials, mainly ceramics, natural and synthetic polymers, and hydrolyzable metals, are designed to dissolve in in vivo through chemical or enzymatic mechanisms and liberate degradation products into their biological surroundings. As opposed to permanent devices, biodegradable implants can preclude the need for secondary surgeries for device removal while circumventing possible long-term health risks associated with permanent implantation.6Li C. Guo C. Fitzpatrick V. Ibrahim A. Zwierstra M.J. Hanna P. Lechtig A. Nazarian A. Lin S.J. Kaplan D.L. Design of biodegradable, implantable devices towards clinical translation.Nat. Rev. Mater. 2020; 5: 61-81Crossref Scopus (170) Google Scholar An increasing number of biodegradable devices are being brought from the laboratory into clinical use, including orthopedic fixation devices, cardiovascular stents, and electronic devices. Despite these relentless efforts in technology translation, there remain open challenges as to (1) the programming of biodegradation mechanisms, kinetics, and device functioning time frame, (2) the dynamic balancing of mechanical degeneration and tissue reconstruction, and (3) the self-adapting of degradation products to selectively incur local immune or regenerative microenvironments (e.g., alkaline ionic products favor apatite formation). Herein lie significant opportunities for adaptive biomaterial products. The surface of a biomaterial plays crucial roles in its adoption within biological environments. Through their surfaces, biomaterials come into contact with the human body and present cues (wettability, topography, curvature, functional moieties, etc.) to elicit various biological effects. As such, the fate of an implant is largely dictated by how well the material-host biointerface is established. Therefore, the engineering of bioadaptive surfaces should be an affirmatory direction toward advanced functional biomaterials. Dynamic chemistries, dominantly supramolecular chemistry, coordination chemistry, and reversible covalent chemistry are instrumental to the design of versatile bioadaptive surfaces. The resulting biointerfaces are critical to achieving drug delivery or cell regulation in response to biological stimuli, such as glycemic volatility, body temperature fluctuations, and regional disparity of pH values, depending on the specific dynamic chemistry utilized.7Ma Y. Tian X. Liu L. Pan J. Pan G. Dynamic Synthetic Biointerfaces: From Reversible Chemical Interactions to Tunable Biological Effects.Acc. Chem. Res. 2019; 52: 1611-1622Crossref PubMed Scopus (36) Google Scholar Even more versatile and superior functionality could be unlocked by incorporating spatial precision to these chemistries, for example, through synergizing with photochemistry, molecular imprinting, and surface patterning or nanostructuring techniques. In addition to functionalized surfaces, implanted materials or devices that have lifelike dynamic hierarchical organizations are desirable so as to more biomimetically restore impaired tissue structures and functions. To illustrate such possibilities through 3D printing using self-assemblies of keratin protein, Cera and colleagues produced hierarchically structured, shape-reconfigurable architectures.8Cera L. Gonzalez G.M. Liu Q. Choi S. Chantre C.O. Lee J. Gabardi R. Choi M.C. Shin K. Parker K.K. A bioinspired and hierarchically structured shape-memory material.Nat. Mater. 2021; 20: 242-249Crossref PubMed Scopus (42) Google Scholar Mechanistically, this was achievable because keratin could reversibly switch between coiled-coil and β sheet conformation to provoke moisture-responsive geometrical changes. In the context of clinical practice, the capability for an implant to assume an adaptive geometry (i.e., shape-memory effect) is enticing to both physicians and patients. For example, miniaturized cardiovascular stents with deployable geometry could streamline interventional treatment, removing the need for follow-up surgery and improving patient outcomes. Another example is shape-morphing bone scaffolds that allow for a minimally invasive, self-fitting surgical experience. To realize such medical devices, it is worth leveraging the potential of meta-biomaterials and 4D printing platforms. As such, Manen et al. custom-modified a commercial extrusion printer, with which they printed reconfigurable constructs consisting of expandable meta-biomaterial unit cells. These constructs permitted high-level geometrical complexity as well as 3D-to-3D shape-shifting behaviors, demonstrating promise as developable medical devices.9van Manen T. Janbaz S. Jansen K.M.B. Zadpoor A.A. 4D printing of reconfigurable metamaterials and devices.Commun. Mater. 2021; 2: 56Crossref Scopus (15) Google Scholar To conclude, we have introduced “precise bioadaptability” as a concept aimed at development of precision medicine. We have provided illustrative examples of how to design and functionalize bioadaptable biomaterials and devices, incorporating one or more of these aspects: biology, mechanics, chemistry, surface, and geometry. Rather than taking on a “one character fits all” approach as popularized in conventional tissue repair, these biomaterials can follow extracorporeal or endogenous triggering mechanisms. This enables their bulk/surface properties and cellular/tissue responses to be tailored across spatial dimensions and timescales, to precisely adapt to the hierarchical organizations and/or dynamic microenvironments of host tissues. Despite the impressive achievements to date, this field is still in its infancy, and numerous challenges remain unresolved. The prime one pertains to the realization of adaptable biomaterials with multiple aspects of bioadaptability, which are seamlessly integrated and spatiotemporally synchronized, with streamlined design to facilitate bench-to-bedside translation. A key to this could be to encode next-generation biomaterials with the capability to simultaneously sense and react to multi-stimuli. As the fields of materials chemistries, engineering, and manufacturing progress, we envisage these challenges to be gradually overcome, leading to bioadaptable biomaterials that will push the frontiers of precision medicine.