Smart Biomaterials: Recent Advances and Future Directions

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Smart Biomaterials: Recent Advances and Future Directions Piotr S. Kowalski, Chandrabali Bhattacharya, Samson Afewerki, and Robert S. Langer ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.8b00889 • Publication Date (Web): 27 Sep 2018 Downloaded from http://pubs.acs.org on September 28, 2018

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ACS Biomaterials Science & Engineering

Recent advances and future direction of smart biomaterials and their applications in tissue engineering, drug delivery and immune engineering are presented. 338x190mm (96 x 96 DPI)

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Figure 1. An overview of the applications of smart biomaterials in the fields of tissue engineering, drug delivery, medical devices and immune engineering. a) Stimuli responsive material for promoting tissue growth and cell differentiation. b) Injectable biomaterial loaded with cells, bioactive molecules or drugs applied in tissue engineering to promote healing of a damaged tissue. c) Swelling of dry solid polymer and its three-dimensional hydrogel network after exposure to water mimicking the extracellular matrix (ECM) in native tissues. d) Shape memory and temperature responsive soft material employed as a tissue gripper. e) Star shaped delivery system for sustained drug release in the gastro-intestinal tract. f) Nanoparticle based stimuli responsive drug delivery system for systemic application. g) The strategy for enhanced cancer immunotherapy using targeted delivery of chimeric antigen receptor (CAR) T-cell. 338x253mm (96 x 96 DPI)


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Smart Biomaterials: Recent Advances and Future Directions Piotr S Kowalski,1,2† Chandrabali Bhattacharya,1,2† Samson Afewerki,1,3† Robert Langer1,2,3,4,5*

1

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.

2

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

3

Division of Gastroenterology, Brigham and Women´s Hospital, Harvard Medical School, Boston, MA 02115.

4

Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

5

Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

†

These authors contributed equally to this work.

*

Corresponding Author Email: [email protected]



ABSTRACT Smart biomaterials have the ability to respond to the changes in physiological parameters and exogenous stimuli, and continue to impact many aspects of modern medicine. Smart materials can promote promising therapies and improve treatment of debilitating diseases. Here, we describe recent advances in the current state-of-the-art design and application of smart biomaterials in tissue engineering, drug delivery systems, medical devices and immune engineering.

KEYWORD: Smart materials, biomaterials, tissue engineering, drug delivery, medical devices, immune engineering.


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1. INTRODUCTION Over the last few decades, innovations in biomaterials have had a tremendous impact on all aspects of medicine transforming tissue engineering, drug delivery, immune engineering, and the manufacture of medical devices. Advances in molecular self-assembly, polymer synthesis, protein and peptide engineering, and microfabrication technologies have introduced nextgeneration “smart” biomaterials, that can be designed to adapt their chemical and mechanical properties in response to changes in physiological parameters and exogenous stimuli.1 These materials are desired for medical and tissue engineering applications, due to their ability to respond to biological, chemical and physical cues, including pH, redox potential, enzyme activity, temperature, humidity, light, sound and stress.2,3 Additionally, some biomaterials display unique mechanical properties such as shape-memory or self-healing behavior. The increasing demand for smart biomaterials is motivated by growing interest in precision medicines tailored to the individual needs of the patients, the emergence of gene and immune therapies and advances in 3D printing technologies, which hold the potential to expand the boundaries of modern medicine.4–6 Here we discuss recent advances in the design and application of smart biomaterials in medicine and tissue engineering. Recent Advances in Application of Smart Biomaterials 1.1. Smart Biomaterials for Tissue Engineering. Tissue engineering is a multidisciplinary field where medicine, biology, chemistry, engineering and material science converge to develop solutions that restore, promote or enhance tissue function.7 It is one of the key areas that benefit from the adoption of smart biomaterials. However, significant challenges for translation to the clinic remain.8 A major limitation towards designing biomaterials for tissue engineering is the lack of fundamental



understanding of the interactions between the material and the cells or tissues. Therefore, the design of materials with the ability to control cellular behavior is very challenging. Recent progress within tissue engineering has focused on the development of smart materials responsive to external stimuli in the context of cellular systems (cell and tissue microenvironment).9 One approach for the design of smart biomaterials for tissue engineering focuses on the incorporation of specific functional groups into biomaterials allowing control over their physical, chemical and biological properties. This will further promote desired functions such as enhanced cell adhesion, growth, and migration.10 Consequently, the synthetic approaches employed for fabrication of smart biomaterials have to be carefully considered and the two relevant strategies are nature- and bioinspired approaches11 or clickbased orthogonal methods.12 For tissue engineering other than mechanical and chemical versatility, the biomaterial should possess cell compatibility. In addition, degradation of the biomaterial following the completion of prompted tissue formation, can improve biocompatibility.13 Hydrogels, three-dimensional (3D) hydrophilic polymeric networks that swell in an aqueous environment, are used in tissue engineering as scaffold and cellular encapsulation systems, and these materials can be modified to mimic the extracellular matrix (ECM) of native tissue.6 The incorporation of specific functional groups within the hydrogel enables control of physical, chemical and biological properties, often introduced using clickbased orthogonal methods,12 due to their simplicity, ease and efficiency. These modifications can render materials responsive to external stimuli,14 where they perform or trigger a specific function or physical and chemical change upon interaction with receptors, enzymes, cells or other stimuli.15,16 The hydrogel structure can be crosslinked using either irreversible or reversible crosslinking


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methods.17 Reversible cross-linking, through physical crosslinking, thermally induced polymer chain entanglement, and self-assembly, enables hydrogels to undergo structural changes in response to external stimuli.18–20 The combination of both reversible and irreversible crosslinking is often important. The irreversible bonding contributes to the structural integrity of the biomaterials and the reversible mostly contributes to self-healing properties. Furthermore, the degradation and stability of the material can depend on the degree of irreversible and reversible bonding. Therefore, the material with only irreversible crosslinking may be limited in terms of the control over advanced properties required for biocompatibility and function. These self-healing and shear thinning systems are now being applied to injectable biomaterials, which are often loaded with cells, biologics or drugs.21 Montgomery et. al. engineered injectable shape-memory biomaterials for the minimally invasive delivery of functional tissues.22 The elastomeric material was microfabricated and upon injection with cells the biomaterial retained its original structure. Subcutaneous injection of this material into cardiac tissue in a syngeneic rat model displayed substantial improvement of cardiac function. Shape-memory and self-healing behavior allow the materials to recover to their original functionality and structure after exposure to desired stimuli (e.g. temperature change or external strain). In general, the self-healing biomaterials could prevent sudden damage to the implant or coating by fast recovery to its original structure providing a suitable microenvironment for tissue ingrowth and cellular migration, and potentially enhancing the tissue-regenerative capability of the material scaffolds.23 The use of shape-memory polyurethanes has been investigated to produce 4D scaffolds, that allow control over cellular action by modulation of strain applied to the cells during temperature induced shape recovery.24



As hydrogels are often used as cellular scaffolds, there is a need for the systems degrading in vivo after cellular integration with neighboring tissue is complete. Biodegradable hydrogel systems typically make use of stimuli-specific cleavable cross-linkers,25,26 which can be cleaved through hydrolysis, proteolysis or disentanglement in response to stimuli.13 Parratt et al. investigated the effect of hydrogel composition on the human bone marrow stromal cell (hBMSC) differentiation into zone-specific cell phenotypes for the generation of human articular cartilage tissue.27 This study showed that a composite multi-layered material scaffold improved hBMSC differentiation into cartilage-like tissue by increasing sulfated glycosaminoglycans (sGAG) secretion and decreased collagen level. The sGAG is an important component in the cartilage ECM promoting mechanical strength of the scaffold. This study demonstrates the importance of combining several biomaterials, each contributing specific property to design a superior material. To enhance cellular function, hydrogels can be functionalized with molecules which mimic interactions found in the cell and tissue microenvironment or can direct cellular behavior. The addition of Arg-Gly-Asp (RGD) (a cell adhesion mediator) to hydrogel materials, can stimulate cellular activities such as proliferation, differentiation, migration and cell growth.10 Moreover, smart biomaterials have been used as tissue glue, bonding and simultaneously promoting the tissue to heal itself through the incorporation of reactive groups such as dopamine based groups and also cell directing groups such as proteoglycans, collagens and fibronectin.28,29 Recently, Wang et al. devised a chondroitin-based tissue glue that helps direct improved tissue repair.29 The methacrylate functional groups within the biomaterial promote the mechanical stability through photopolymerization, and the aldehydes facilitate tissue integration and adhesion through a Schiff base reaction with the amines on the tissue surface.


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Furthermore, the design of smart materials for tissue engineering applications can benefit from employing 3D printing technologies enabling facile and reproducible fabrication of biomimetic scaffolds to promote better tissue formation and integration with the host postimplantation. The controlled structural features of the printed scaffold can be fabricated with the desired geometry and porosity suitable for the intended use. Among different types of 3D printing techniques, extrusion-based and inkjet-based 3D printing methods are most commonly used for bioprinting.30 To date, modern 3D printers have been used to fabricate complex multicellular tissues including functional bone grafts, liver scaffolds, ovaries, and aortic valves.31

1.2. Smart Biomaterials for Drug Delivery and Medical Devices The US market value for drug delivery products is estimated to reach $251 billion in 2019.32 Drug delivery system can be used to modulate drug pharmacokinetics, absorption, toxicity profiles, and the duration of the therapeutic effect.33 The use of smart biomaterials allows control of the behavior of drug delivery systems (DDS) in response to changes in physiological parameters often associated with different types of diseases and administration routes (e.g. pH, redox potential and enzyme activity), or respond to exogenous triggers such as ultrasound or temperature.15,34 With the advent of precision medicine,4 theranostics, and oligonucleotide-based therapeutics, there is a growing interest for DDS fabricated with smart materials.35–37 A plethora of biomaterials, including polymers, lipids, proteins and peptides are being employed to engineer DDS across different length scales, from nano- (1 cm), for a range of application routes (e.g. enteral, parenteral and topical).38,39 DDS are often engineered from



chemical components with different responses to various stimuli. These can promote degradation and release of the drug in the local microenvironment such as tumors and inflammation sites.40,41 In addition, triggered degradation allows the removal of DDS components from the body and prevents accumulation of potentially toxic metabolites upon repeated administrations. For instance, a hydrogel was recently engineered for long term controlled release of drugs in the stomach, which could be made to dissolve in the case of complications upon exposure to a biocompatible chelator and reducing agent.42 The sensitivity to single stimuli can enrich therapeutic delivery to sites of disease but the rare presence of individual biomarkers often leads to suboptimal selectivity. For example, the cancer microenvironment often displays extensive matrix metalloproteinase (MMP) activity with characteristic reduction potential and sub-physiological pH.43 To address this challenge, implementation of multi-stimuli responsive biomaterials may find utility by improving the selectivity of drug release from DDS in complex disease microenvironments enabling personalized treatment. Bandeau et. al synthesized multi-stimuli responsive crosslinkers, enabling preparation of hydrogels via strain-promoted azide–alkyne cycloaddition (SPAAC) click chemistry.44 These crosslinkers were engineered with a controlled molecular architecture to display logic-based stimuli-responsiveness in the presence of MMPs, reducing species, and nearultraviolet light. In another example, Kwong et. al. developed protease-sensitive synthetic biomarkers for multiplexed urinary monitoring for a range of diseases including liver fibrosis and cancer, that allow sensing the activity of multiple MMPs.45 These biomarkers include peptide substrates selectively recognized by disease associated proteases and can be targeted to disease sites using nanoparticles, subsequently detection of biomarker degradation products in the urine by mass spectrometry or enzymatic methods.46


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Oligonucleotide technologies, which include antisense oligonucleotides, short interfering RNAs (siRNAs), messenger RNA (mRNA), and genome-editing CRISPR therapeutics, are on the path to become a major platform of drug development alongside small molecules and current biologics.5,47 Delivery remains one of the main challenges to fully realize the potential of nucleic acid based therapeutics due to their limited bioavailability and the requirement for intracellular delivery.5,47 To facilitate effective intracellular delivery of nucleic acids, nano-DDS are often engineered with pH-responsive biomaterials such as lipids or polymers containing ionizable functional groups, including tertiary amines and zwitterions.48,49 Tertiary amines undergo protonation in the weakly acidic pH of endosomal compartments (pH 6.0−6.5) helping to facilitate intracellular release and potentially limiting the toxicity associated with cationic carries.50,51 Additionally, charge altering oligo(α-amino ester) were designed that can deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of the functional cargo.52 In addition, DDS with the ability to interact with serum proteins at physiological pH (7.4) have demonstrated the influence of a protein corona on their tissue distribution and cellular uptake.53 Exploiting the natural tropism of DDS can serve as a tool to introduce passive tissue-selective delivery but requires a better understanding of the interactions of biomaterials with serum molecules, cells, and cellular receptors. Thus far, ionizable lipids and lipid-like compounds were shown to interact with apolipoprotein E (APOE) which facilitates efficient delivery of nucleic acid into liver hepatocytes.53–56 Examples of other approaches, such as nature-inspired highdensity lipoprotein mimetics or albumin-based DDS directly incorporate apolipoprotein A1 (APOA1) or albumin into nanocarrier compositions to modulate pharmacokinetics, toxicity,57–59 promote uptake by macrophages residing at atherosclerotic plaques,60 or by antigen presenting



cells (APC) in the lymph nodes. Recently Shamay et. al reported selective caveolin-1 mediated uptake of self-assembling drug containing nanoparticles in tumor cells. The self-assembly of these hydrophobic drug-based nanoparticles formed with the aid of sulfated indocyanines was predicted using a computation algorithm, called quantitative structure-nanoparticle assembly prediction (QSNAP). This introduces a strategy integrating computational approaches in predicting the design of DDS and potentially its interactions with biological systems.61 Patient compliance is one of the most significant challenges in the drug delivery field. One potential solution is maintaining therapeutic drug levels by sustained release, which often requires modular design of DDS. Smart biomaterials have been important for engineering DDS that have to perform complex functions, facilitated by their geometrical and mechanical design, as well as material properties. Orally administered star shaped DDS created for ultra–long-acting oral delivery of antimalaria drugs in the stomach could sustained therapeutic drug levels for two weeks. These stars were engineered from polycaprolactone (PCL) into desired geometrical arrangements from flexible and rigid elements to enable folding of the device into a capsule. Moreover, the components of the star were linked by pH-dependent copolymers (Eudragit), to provide dissolution via fracture at designed failure points in the presence of intestinal pH.62 Precise control of blood glucose levels for patients with type 2 and type 1 diabetes is extremely challenging and often associated with inconvenient daily insulin injections, as well as the risk of hypoglycemia. Shear thinning and glucose-responsive hydrogels can provide sustained release of insulin for 48 h, with the release rates dependent on the glucose concentration. The shear thinning properties of these hydrogels are achieved by dynamic covalent bond formation between phenylboronic acid and cis-diol modified polyethylene glycol (PEG) monomers allowing their subcutaneous injection.63 Furthermore, a hyaluronic acid-based microneedle patch integrated with


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pancreatic β-cells, capable of stabilizing glucose levels for over 10 h in mice could provide yet another alternative to insulin injections. Insulin secretion from β-cells in the patch in response to hyperglycemia was possible due to an enzymatic cascade of glucose oxidase, α-amylase and glucoamylase entrapped into pH sensitive polymeric vesicles in the microneedles, enabling amplification of the glucose signal.64 With the continuous decrease in the cost of oligonucleotide synthesis, the use of DNA building blocks poses an attractive approach for engineering multifunctional 3D nanostructured DDS. Taking advantage of predictable interactions (Watson–Crick base pairing), DNA nanostructures display an unprecedented ability to be programmed to any size, shape and ligand patterning, and are compatible with numerous chemistries for stabilization and biological compatibility. They can also be designed to release their contents in response to specific biological cues, including protein and oligonucleotide binding.65 Despite important hurdles for the application of DNA nano-structures in drug delivery, such as limited in vivo stability, the need for endosomal escape and their potential immunogenicity, DNA nanostructures show potential to advance the area of drug delivery. Thus far, DNA origami structures were shown to encapsulate antibodies and release the encapsulated cargo following recognition of a specific protein on leukemia cells by aptamer hinges.66 In another study, DNA nano-cages were able to selectively deliver and release siRNA cargo inside the cells upon recognition of a specific microRNA (miRNA) sequence.67 Smart biomaterials have the potential to revolutionize fabrication of medical devices, due to advances in biomaterial design, functionalization, as well as the development of 3D printing and other processing technologies. Smart medical devices incorporate stimuli-responsive materials either on the surface or as part of the bulk design of the device. Shape-memory polymers are a leading class of biomaterials that can potently impact engineering of medical devices. Polymer



with dual shapes,68,69 triple shapes,68–70 and multiple shapes have been developed68,71,72 potentially enabling multitasking capabilities.72 Gracias et al. have engineered thermo-responsive theragrippers, composed of biodegradable rigid poly(propylene fumarate) segments and hinges made of poly(N-isopropylacrylamide-co-acrylic acid).72 The device utilizes both a mechanical and chemical approach to grip the tissue at body temperature with its sharp tips, following a shape change and then releasing a drug in a localized and sustained manner for up to one week. 3D printing enables manufacturing medical devices with different geometric forms, sizes, and shapes. Qi and coworkers reported 3D printing of flexible materials with shape-memory and selfhealing properties presenting high stretchability (up to 600%) for potential use as a vascular repair device.73 The authors employed an ink mixture composed of PCL and photocurable urethane diacrylate (isobornyl and n-butyl acrylate) components, and utilized a 3D printing method combining a direct-ink-write approach and UV curing steps. For implantable medical devices such as catheters and orthopedic implants, accumulation of microbes on the device surface is considered a serious issue and potential health hazard. Consequently, device surface modification with biomaterials possessing antimicrobial properties capable of self-cleaning and triggered release of antimicrobial agents, can help minimize or prevent device infections. Jiang and coworkers reported environmental pH responsive-copolymers coated with zwitterions, composed of quaternary amine monomers (positively charged) and carboxylic acid monomers (negatively charged).74 This copolymer coating was found to switch between bacteria-adhesive and bacteria-resistant forms in response to pH changes, allowing detection and removal of inactivated microorganisms. A comprehensive summary of recent advances in antibacterial surface designs with dual-function strategies and their combinations was reported by Yu et al.75 2.3. Smart biomaterials in Immune Engineering


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The immune system plays a pivotal role in maintaining homeostasis and the resolution of disease in the human body. Nevertheless, it also adversely reacts to the use of biomaterials, recognizing their foreign origin, often resulting in negative immune responses which can interfere with any kind of transplant, medical device or drug delivery system. Thus, a major challenge is the lack of understanding of the interactions involved between immune components and biomaterials. Development of smart biomaterials has however made it possible to modulate the immune system. Prevention of negative immune responses is particularly critical in case of material-based implants. For implanted objects, the foreign body response is primarily a two-step process comprising of an inflammatory reaction followed by wound-healing76 that triggers deposition of a thick layer of collagen covering the implant.76–78 Hence, the efficacy of implanted biomedical devices is often compromised, especially in the case of encapsulated live cells. One such example is the use of pancreatic islet cells for the treatment of type 1 diabetes, where fibrosis surrounding the device interferes with the nutrient supply and exchange of waste products resulting in cell death.76,79 For decades, the search for both anti-inflammatory and anti-fibrotic materials has been extremely challenging. In the synthesis and subsequent screening of a large combinatorial library of chemically modified alginates, Vegas et. al. discovered three lead candidates that were capable of resisting immune response and consequently prevent fibrosis in rodents and non-human primates.80 Each of the three contained triazole functional groups. These materials permitted the development of an antifibrotic surface of microcapsules containing islets allowing proper nutrient supply maintaining normoglycemia for up to six-month period. Over the past decades, development of immune-interactive smart materials has dramatically



increased enabling critical understanding of the mechanism behind the immune response. Remarkable progress has been achieved in the field of biomaterials with intrinsic immunogenicity and the variation in shape, size, and chemistry of these materials, which can be harnessed to improve responses toward vaccines and different immunotherapies. Various classes of biomaterials including polymers or lipids modified with photoactive, pH sensitive or other reactive groups has helped in delivering therapeutic cargoes to immune cells.81–84 Additionally, triggered release of microneedle arrays have been used for skin immune cell targeting.85,86 A better understanding of intrinsic immunogenicity will provide a means to elucidate how to modulate and re-engineer immune pathways essential to delineate further the development of next-generation materials for vaccines or immunotherapy. Additionally, the different particle geometries influences the interaction of antigen-presenting cells (APCs) with immune cells that is a critical determinant of their effector functions and can be modulated to develop more advanced designs.87–89 Recent efforts have also focused on the activation of a patient’s immune system to fight cancer, termed as cancer immunotherapy, utilizing controlled targeted delivery of small molecules, antibodies or nucleic acids. This technology has emerged as a highly effective cancer treatment strategy in comparison to traditional therapies having much higher remission rate for advanced stages of certain cancers, and smart biomaterials can potentially further promote immunomodulation for personalized cancer treatment. A series of studies by Stephan et. al. underscored the design of a bioactive polymeric implant scaffold integrated with collagen-mimetic peptide unit (CMP) that binds to the surface of lymphocytes and is able to deliver, expand and disperse T-cells reactive to tumors.90 Strengthened by an arsenal of smart T-cell deposits, this approach can potentially be used to treat tumors previously inoperable or


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incompletely removed. More recently, Tang et al. demonstrated the utility of antigen-specific T-cells in backpacking interleukin-15 protein nanogels responsive to the change in T cell surface

reduction

potential,

resulting

from

antigen

recognition

in

the

tumor

microenvironment.91 In another example, Wang et al. developed an inflammation-triggered immunotherapeutic comprised of DNA nano-cocoon having CpG repeating units encapsulating anti-PD-1 antibody and a restriction enzyme responsive to inflammation.92 Upon reaching the pro-inflammatory microenvironment of the tumor, the restriction enzyme digests the DNA releasing anti-PD-1 checkpoint blockade antibody and CpG DNA that further activates dendritic cells to enhance the T-cell response. Furthermore, biomaterials offer unique opportunities to modernize vaccines. One of the main issues with engineered vaccines is the requirement of repeated injections of adjuvant in a timescale promoting production of memory T-cells that help to recognize of specific antigens during future infections. One way to potentially tackle this problem is by creating smart materials that can in a single injection release the vaccine in a pulsatile fashion over time to maximize efficacy. The solution is of particular interest in places where access to medical care is limited, especially in rural Africa, and patients are sometimes unable to complete the full course of immunization. Recently, McHugh et al. developed a method to encapsulate different vaccines in a polymeric system having above delivery characteristics.93 They developed a new microfabrication method called StampEd Assembly of polymer Layers (SEAL), to produce micrometer-sized capsules with nearly any geometry that can hold the vaccine molecules within the particle core. These bio-degradable poly-lactic-co-glycolic acid (PLGA) microparticles were filled with biologics and sealed with a cover lid that degrades at different predetermined selected



times to release the vaccine payloads. Using this approach, multiple PLGA particles with different ratios of lactate:glycolide in their core could be co-injected as a single dose at the time of the initial immunization and programmed to degrade releasing antigen in a discrete pulsatile fashion over time matching conventional vaccination time-points.

CHALLENGES AND FUTURE DIRECTIONS

One goal in the field of smart materials and their application in tissue engineering, drug delivery, immune engineering and medical devices is to develop materials that are biocompatible and are able to respond to external signals or the surrounding environment. In tissue engineering, smart materials should not only mimic the ECM but also be able to interact with tissues and cells promoting adhesion or being able disintegrate on demand, while in drug delivery, smart materials could provide tissue selective and stimuli responsive delivery over prolonged periods of time, followed by clearance from the body after completion of their task. In immune engineering, smart materials should provide targeted delivery to immune cells and/or prevent negative immune responses or unwanted inflammation. However, the design of smart materials which combines several of these properties is a challenge. For example, it can be challenging to develop a smart material with optimal mechanical and chemical properties without negatively influencing biological properties. In this context, mimicking nature and gaining a better understanding of its fundamentals, could promote the development of bioinspired materials with unique biological properties for biomedical applications.94 Additionally, looking beyond naturally available biomaterials and exploring cutting-edge chemistries and fabrication technologies, can lead to development of novel synthetic biomaterials. Smart materials obtained from natural products such as polysaccharide Xanthan


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gum or gelatin, have the benefits of biodegradability, biocompatibility, cell recognition sites, and often display optimal physical-, chemical- and mechanical properties. However, challenges associated with the use of biologically derived materials such as collagen, involve tedious purification procedures and potential immune responses. Synthetic biomaterials can overcome many of these challenges enabling the design of materials with desired properties tailored towards specific applications. However, the lack of biocompatibility and potential long-term side effects of novel synthetic materials can cause negative effects. In this regard, the material should not only be degradable but the degradation products must be nontoxic and biocompatible. In addition, for smart biomaterials used to fabricate medical devices the development of efficient and safe sterilization, packaging and storage methods with minimal impact on the thermomechanical properties and performance of the polymeric components needed to be addressed. One example of a future smart material would be a material that is so smart that it actually can interpret and respond to the complex signaling mechanisms in our cells, tissues, or body, allowing it for instance to detect and react to malignant changes at the cellular level at an early stage of cancer development. Future efforts should also focus on better understanding the interactions of biomaterials with the body, to help develop better immunoprotective biocompatible materials, utilizing bioorthogonal and biocompatible chemistries for biomaterial synthesis such as living polymerization and click chemistry, along with incorporating natural or biocompatible building blocks (e.g. natural metabolites, GRAS substances) and degradability features into biomaterial design.95 One approach to gain a better understanding of the interactions between the material and the cells could include decreasing the complexity between these two components and employing simple in vitro or in vivo models to quantify the desired interaction. For example, some of the functional groups of the material could be protected or modified, allowing identification of the key entities involved in



modulating cellular contact or behavior, that could be further measured by reporter assays coupled to the activity of specific cellular pathway (e.g. inflammation, proliferation). Moreover, the integration of computational models of the surface chemical structure of the material could also promote better understanding of these interactions. To ensure better translation of preclinical studies involving smart biomaterials to the clinic, a number of factors should be considered including regulatory and manufacturing constrains (e.g. material complexity, ease of scalability, batch to batch reproducibility), consistency in material performance and its biocompatibility over time. Smart biomaterials that contain a mixture of biologics, drug or tissue entities, each having its own distinct regulatory pathway, may face regulatory and manufacturing challenges and struggle to demonstrate high level of consistency in patients. In tissue engineering, smart materials can have further impact in 3D printing of organs promoting stable and facile printing with enhanced integration with host tissue avoiding rejection and inflammation. In addition, the use of computational and machine learning technologies can potentially impact the design of biomaterials and improve prediction of their interactions with physiological components including serum proteins, cell membranes, and cellular receptors.

Acknowledgement We would like to thank Dr. Shady Farah for his valuable discussion and input. We thank Dr. Derfogail Delcassion for proof reading the manuscript. Dr. Piotr Kowalski acknowledges funding from the Juvenile Diabetes Research Foundation (JDRF) postdoctoral fellowship Grant 3-PDF2017-383-A-N. Dr. Chandrabali Bhattacharya acknowledges the Juvenile Diabetes Research


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Foundation (JDRF) postdoctoral fellowship Grant 3-PDF-2018-576-A-N. Dr. Samson Afewerki acknowledges financial support from the Sweden-America Foundation (Familjen Mix Entreprenörsstiftelse), Olle Engkvist Byggmästare Foundation and Swedish Chemical Society (Bengt Lundqvist Memory Foundation).

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Figure 1. An overview of the applications of smart biomaterials in the fields of tissue engineering, drug delivery, medical devices and immune engineering. a) Stimuli responsive material for promoting tissue growth and cell differentiation. b) Injectable biomaterial loaded with cells, bioactive molecules or drugs applied in tissue engineering to promote healing of a damaged tissue. c) Swelling of dry solid polymer and its three-dimensional hydrogel network after exposure to water mimicking the extracellular matrix (ECM) in native tissues. d) Shapememory and temperature responsive soft material employed as a tissue gripper. e) Star shaped delivery system for sustained drug release in the gastro-intestinal tract. f) Nanoparticle based stimuli responsive drug delivery system for systemic application. g) The strategy for enhanced cancer immunotherapy using targeted delivery of chimeric antigen receptor (CAR) T-cell.


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For Table of Contents Use Only

Smart Biomaterials: Recent Advances and Future Directions Piotr S Kowalski,1,2† Chandrabali Bhattacharya,1,2† Samson Afewerki,1,3† Robert Langer1,2,3,4,5*

1

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.

2

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

3

Division of Gastroenterology, Brigham and Women´s Hospital, Harvard Medical School, Boston, MA 02115.

4

Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

5

Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

†

These authors contributed equally to this work.

*

Corresponding Author Email: [email protected]

Synopsis Recent advances and future direction for applications of smart biomaterials in tissue engineering, drug delivery and immune engineering are presented.


Smart Biomaterials: Recent Advances and Future Directions

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