Dear Zhenwei Ma and Jianyu Li,

Thanks for taking up the discussion on adhesion and moving towards mechanotransduction. I really enjoyed your post.

For a cell to probe the mechanical properties of the matrix, integrins first attach to the matrix ligand(adhesion). For example, integrins can bind to RGD of the matrix. Then they probe the matrix mechanical properties at a some frequency. Depending on the properties they sense, integrins can cluster and a cascade of signalling events occur inside the cell all the way up to translocation of YAP proteins inside the nucleus which can affect the genes, etc. Now with viscoelastic matrices, things get complicated. To make it simple, people used stiffness as a paramter and studied how cell behavior changes with stiffness. As you pointed out, Mooney and Chaudhuri's group worked on time dependent aspects. Also recently Paul Janmey's group works on viscoelastic solid like matrices. In addtion to this, there are papers which say the pore size of the gel determines cellular mechanotransduction. This is because the pores present adhesive ligands (RGD) at different spacings. Also, the beauty of mechanotransduction is it is is biphasic. Matrix affects cell behavior -> also cells can degrade the matrix. For example, in Ovijit chaudhuri's group one of the reason they say for differences in cell spreading is that, cells remodel the matrix when you have a relaxing matrix.

Now coming back to adhesion, doesnt adhesion would mean different things for cells and tissues, isnt it? Does a highly adhesive material would really matter to cells since they care more about the underlying mechanical properties and they anyway want to attach and spread to the matrix ligands? Or am I missing something here?

In this case, how do you think we can use tissue adhesives for cellular mechanotransduction studies?

Thank you Jianyu for such a helpful reply! Hope to see more exciting research from your group on this topic!

Thank you Jianyu. We only focus on the demonstrations of mechanics part and move on without pushing the material into real applications. We hope experts on biomaterials like you can use the strategy to develop materials closer to applications.

Thanks, Ruobing. Indeed, the mechancially instrusive biomaterial is part of mechanobiology. It has a special focus on the central role of man-made materials, compared to other studies in mechanobiology.

Thank Tongqing and congratulations to you on another great paper. We have been following your work include this recent one. Indeed, your approach has successfully raised the interfacial fatigue threshould. It is very exciting to see that the design and effect of elastic dissipators aligns well with the Lake-Thomas model. For tissue adhesion, further development is required to extend your design onto the tissue surface in a biocompatible manner.

Hi Jingda,

Thank you for your support and questions. I am not the pioneer but in fact stands on the shoulders of giants, including Nikolaos Peppas, Antonios Mikos, Robert Langers, Jeff Karp and many others.

1. Living tissues pose stringent requirements to the tissue adhesives in term of long-term adhesion in vivo. As stated in the journal club, tissues are renewing or regenerating constantly. Interestingly, this rate varies dramatically with diffferent tissues, for instance, the heart tissue renews in tens of years while the skin renews in weeks. To this end, suturing is safer because the suture penetrates deeply through tissues forming nearly permentaly interlocking for adhesion, unless the suture itself is degradable. Therefore, the suture and suturing remains indispensible for many surgical procedures, depsite the development of tough and strong adhesives.

The long-term evaluation of adhesives in vivo remains limited. They are typically tested in rodent models for weeks. Some exceptions include a work from Jeff Karp (6 months on heart; Sci. Transl. Med. 6 (218), 218ra6) and a recent work from Huajian Gao (1.5 year on heart; Nat. Biomed. Eng. 3, 632–643(2019)). Both are rodent models again as long-term large animal models are expensive to conduct.

2. Yes, the aldehyde glue is "surprisingly" approved for the inner body use. Many other adhesives are used in clinics, on which and translational aspects are nicely summarized in a recent Nat. Rev. paper by Yuhan Lee and Jeff Karp (Nat. Rev. Mat. 5, 310-329, 2020).

3. The adhesion on skin has been extensively studied, and skin is often used as a model tissue surface for testing. Opportunities remain on achieving on-demand attachment and detachment on skin especially impaired skin like those of diabetic or burn patients.

Dear Jianyu,

Thank you for discussing this interesting new direction combining mechanics, chemistry, and biology. Could you give some comments on comparing mechanically instructive biomaterials and mechanobiology? To me, mechanobiology means studying how mechanical signals change the evolotion/development of biological materials.

Sincerely,

Ruobing

Dear Jianyu,

Thanks for your timely and insightful review. I have just started to work on this interesting field, mainly focusing on the mechanics part. We notice one of your recent work reported that the interficial fatigue threshold of Ca-Alginate tough hydrogels was 24 J/m2, far below its adhesion energy. We understand the result as follows: tough adhesion of Ca-Alginate/tissue is achieved by using inelastic dissipators, that is, the ionic bonds.However, the inelastic dissipaters work only once and fail to enhance adhesion under prolonged cyclic loads.

Our recent paper reported that: tough and fatigue-resistant adhesion can be achieved by using a particularly simple kind of elastic dissipaters: long-chain polymers. Each polymer chain is elastic before rupture. When a single covalent bond of the chain breaks, the elastic energy stored in the entire chain dissipates, amplifying the adhesion energy by the number of links on the chain. So far as the adherends provide the stiffness of an adhered sample, the adhesive can be made of polymer chains of extremely long length.

As a proof of concept, we use polyacrylamide hydrogels to adhere two pieces of polyester cloth through topological entanglement. We find that both the adhesion energy and fatigue threshold increase with the polymer chain length and can reach 1400 J/m2 and 300 J/m2, respectively. The measured fatigue threshold of adhesion is linearly proportional to the square root of the chain length, in agreement with the Lake-Thomas model. This fatigue-resistant design can be extended to a variety of adhesion topologies for different adherends and adhesives.

The paper can be found at: https://doi.org/10.1016/j.eml.2020.100813

Dear Jianyu,

Thank you for the timely review on hydrogel adhesive. Since you are the pioneer in this field, I have some questions looking for your perspective:

(1) We have been talking with surgeons these days. They firmly believe in hand-suturing, because suture can sustain for a very long time (months to years), which is necessary for the healing of tissues. What is the long-term performance of the developed hydrogel adhesive in vivo? Is there any investigation on this?

(2) In the search of literature, we find that the gelatin-resorcinol-formaldehyde (GRF) glue had been a popular system and had been used to treat diseases in Europe, since it can instantly bond to tissues. Are there any other hydrogel adhesives really used in clinic surgery?

(3) A lot is known about the skin adhesive, I wonder what is the state of art about the hydrogel adhesives used in vivo?

Thank you Jianyu for your insight! I agree with you. Despite the huge success in making strong tissue adhesion, there are still many aspects requiring further investigation which will be exciting and impactful in terms of both scientific understanding and translational applications. To promote the use of recently designed tough adhesives, mechanicians, materials scientists, and clinicians will be working more closely to bridge the gap. I am looking forward to your subsequent exciting work.

Dear Jason,

Thanks for your comments. Indeed, as you pointed out, more than one properties come into a game for real-world applications. Compared to engineering applications, the design space is particularly large beyond mechanics, and considerations are many for biomedical applications, as interfacing with the human. A nice example is illustrated in a very recent publication from Eben Alsberg and Ali Khademhosseini in Science Advances, on combinatorial screening of biochemical and physical cues for cartilage repair (Junmin Lee, et al. Sci. Adv. 6, eaaz5913, 2020). While conventional paradigms are slow and expensive, a trending topic lately is combination of high-throughput techninques and AI.

In my perspective, publications in materials science and mechanics tend to focus on a specific property (e.g., extreme properties such as adhesion or toughness), whereas the work in translational medicine has a bigger picture and placed more emphasis on translationability.

Regarding the killer applications of the recently developed adhesives, it is an open question calling for more translational efforts. In light of Xuanhe's recent talk, the repair of lung and gastrointestinal tract is within his radar, while we are interested in orthopedic applications such as cartilage and intervertebral disc repair.

Dear Jason,

Thanks so much for your comments! I think both the tough adhesives and dry double-sided tapes are potentially excellent tools for wound closure (to prevent liquid/gas leakage; function as mechanical barrier like skin) and trauma management (e.g. battlefield injuries), for healthy individuals with good regenerative capabilities. There're certainly other drastically different and demanding design requirements for implantable applications, as they're expected to be minimally invasive and ideally biodegradable. And it is a whole different story for patients with various pathological conditions. I believe that the above two work demonstrated one's ability to achieve unprecedented hydrogel-tissue integration, so it should be ralatively easy to fine-tune it to an appropriate level for future need-based mechanotherapy. I totoally agree that the next steps would be to work with medical professionals, where some of the healthcare challenges might be solved via mechanical engineering approaches (hopefully!).

Dear Hyunwoo,

It is indeed a challenging yet fascinating field! It might take some trial and error, but I still believe that it's much easier for a mechanic/mechanician to transit to biomedical engineering than the other way around. Good luck with your future endeavours!

Dear Zhenwei and Jianyu,

Thank you for your timely and insightful review of biomaterials in medical applications! The idea of mechanically instructing biology to behave in a certain way is fascinating. I have the following question:

It seems that a mechanically instructive material requires the confluence of multiple properties for it to be effective in clinical applications. For example, an ideal wound dressing would tune the properties, such as adhesion energy, properties for tissue repair (e.g., relaxation time, stiffness, etc), stability (e.g., resistance to swelling/drying and chemical degradation), and lifetime, for a particular application. Dressings for the skin may require high adhesion energy and resistance to dehydration, whereas dressings for internal organs may require the opposite. Is this a significant barrier for implementing new tissue adhesives, such as yours and Xuanhe's, in clinical settings? Does one property fail while another is made extreme? Or, is it good enough to optimize the critical properties, such as tough adhesion for a battlefield injury and tissue repair for stationary inpatient care? In either case, I see the next step is to identify key problems in medicine, which will likely require collaboration with medical professionals.

Thank Jiawei for the comments. You raised very good questions, which call for synergistic efforts of researchers from different areas.

1. Adhesion is for immediate integration between biomaterials and tissues, or to approximate tissues together for wound closure. The level of adhesion depends on certain applications, on which no guidelines have yet been established. A common criterion, which is debatable, is based on the adhesion properties of native tissues of target, for instance, a often-cited value for the interface between cartilage and bone is around 1000 J/m-2, and that of different layers of skin is around 300 Jm-2. Unfortunately, such properties related to interfacial fracture of biological tissues are not often reported in literature. To this end, we are currently exploring the fracture properties of blood clots and intervertebral discs with surrounding tissues.

In addition to the adhesion properties, the driving force presented in vivo to cause debonding, i.e. energy release rate G, remains elusive. For instance, what is the G applied onto the adhesive patch when a heart is beating? Such calculations can be performed with some simple cases. However, given the complexity of the geometry, properties, stress/strain fields of biological tissues, the determination of energy release rate associated with certain tissue movements such as heart beating, joint movements and spine loading is non-trivial. It calls for further development in theory, modeling and characterization.

Lastly, in vivo study with varying adhesion levels is required to answer the questions. It can be expensive but clearly feasible as the in vivo experiments routinely investigate the effects of varying drug dosage, etc.

2. Indeed, those hydrogels you pointed out have been extensively studied in vitro. Toward in vivo applications and clinical translation, concerns persist particularly for the polyacrylamide, which is arguably the most widely used polymer for tough hydrogels. In my opinion, the toxicity and regulation concerns with polyacrylamide necessitates the use of other FDA-approved polymers such as polyethylene, collagen and gelatin gels. This step is important to make real-world impacts.

Dear Jianyu,

This is a really nice summary of various designs of biomaterials used in emerging biomedical applications. I have two questions looking for your insight.

1. You mentioned viscoelastic properties of hydrogels have influences on cell behaviors. Then for the hydrogel-tissue adhesion in the body, how do you envision the hydrogel or the adhesive layer affects the cell behaviors (development, proliferation, maturing, function, etc.) in the adhered tissues? Strong adhesion is good for mechanics, is it also good for biology? How strong is enough to accommodate the two properties and any ways to characterize?

3. Synthetic hydrogels like polyacrylamide, poly(acrylic acid), poly(vinyl alcohol) hydrogels are biocompatible and have long existed. They have been engineered to exhibit many remarkable mechanical and biomedical capabilities much beyond traditional biopolymers. However, their clinical applications are still very limited. Do you think what is the barrier to the wide-use of these hydrogels in clinical settings? And any thoughts about how to overcome the barrier?

Dear Zhenwei,

Thank you so much for sharing your thoughts! It is very insightful. Yes, I fully agree that the pursuit of extreme properties in mechanics studies sometimes does not fit well for biomedical applications. That's also exactly what I felt when I am making a transition to biomedical domains. Engineering of properties in mechanics and materials studies often blindly aim higher or lower numbers at the price of many other properties become imbalanced (biocompatibility, biodegradability, and other mechanical or biological properties). Hence, it is common to find that the best material in terms of a certain property is actually not the best choice for biomedical applications in which such property is required. It is very interesting to find that, in some sense, too much optimization of individual properties can be redundant when it comes to biomedical applications!

Thanks Hyunwoo for your comments! I'm a big fan of you and Xuanhe's work. Looking forward to your next steps! I know your questions are directed to Jianyu, but I hope I could comment on it as well if it's okay.

My impression is that in the world of mechanics/materials, it's an endless pursuit of the extreme (the toughest, the strongest, etc.). In the biomedical/clinical settings (physiological or pathological), however, apart from finding the right questions, defining the suitable properties to be designed is also very challenging. That's why I feel that biomimetic or bioinspired strategies would potentially work well for biomaterials development. As mentioned by Jianyu, both cardiac and neural tissues are very sensitive to mechanical, electrical and chemical stimulus. Designing a fully integrated system to control all the multi-physical interactions would be ideal, but can be too complicated (and expensive) to be implemented in the clinics. Sometimes, "good enough" might just be better.

Thanks Guangyu! Indeed, there have been numerous interesting in vitro studies illustrating how materials with well-defined mechanics can regulate biological behaviors. The accountable biointegration enabled by tissue adhesives would allow us to intimately alter the local biomechanical microenvironment. This is an exciting direction to explore.

Thanks, Guangyu. Many recent works have mainly focused on the formation of adhesion itself. While this is somewhat addressed, the next step is to customize the biomechanical properties of the adhesive matrix for promoting the biological systems to heal, for instance, viscoelasticity to assist cellular activities. There might be coupling between the interfacial and bulk properties of the adhesives. As such, the optimal condition for adhesion and cellular activities is not necessarily matched. To this end, multilayered designs that incorporate an adhesive layer and other functional layers, as demonstrated by Xuanhe and Hyunwoo, may be one of potential solutions.

Dear Jianyu,

Thank you so much for sharing your thoughts! I fully agree that there is a stiff learning curve to transfer mechanics and materials focused knowledge into biomedical applications. Hope there can be some kind of systematic strategies for such rewarding yet tough transition as the field grows over time.

Dear Hynwoo,

Thanks for your positive comments. We are also learning a lot from your and Xuanhe's works, which are leading the field. Regarding your questions, I don't have a perfect answer but would like to try:

1. Translation work is never easy and we are learning as well. Accoring to Xuanhe's recent talks, you have made much progress toward this direction. The key solutions, as pointed by many pioneering researchers, include talking with clinical researchers to identify the right problem and learning their "languages" to present the solutions. Most often, the process involving in vivo work is often slow, lengthy and full of suprise, compared to the research activities in mechanics and materials where more things are understood and controlled. Thus, it takes more patience and might derserve adapting the mindset of being a bioengineer, instead of a mechanician, when doing such projects.

2. Indeed, the electrical modality is a critical element in addition to the mechanical ones shown above. There are many recent publications that incorporate electrical conductive materials into adhesives for the cardiac and neural applications, including your latest work on Nature Communications and another one on Adv. Mater. (30, 23, 1704235, 2018).

Dear Jianyu,

It is a very nice review of the emerging field in hydrogel and soft materials. I do have enjoyed your works a lot and look forward to more. I have a couple of points for which I am curious how you think:

1. We are also actively working on more translational developments and applications of bioadhesive technologies recently - but unlike our previous works, translational biomedical engineering has given us lots of new challenges. We have seen tremendous chasms between bench-top development based on mechanics, material science and engineering, and clinically relevant applications in practical setups. How do you think on possible ways to alleviate this stark gap for mechanics and materials researchers? I feel this is one of the central challenges in this promising emerging field.

2. Apart from mechanical interactions, how do you think of the possibility of other modalities like electrical communications? While mechanical properties and their roles in interaction with biological tissues are still not fully explored, biological tissues possess rich set of multi-physical interactions often highly coupled with each other.

Dear Zhenwei and Jianyu,

Thank you for providing this concise and nice review! Tough adhesives currently are mainly used as mechanical supports but are usually bioinert. The AAD matrix is definitely a milestone in the design of biologically active adhesive systems. It would be exciting to incorporate other instructive cues, such as mechanotransductions, into the tissue adhesive design to provide active support on the cellular level.