Self-Healing Injectable Hydrogels for Tissue Regeneration

Biomaterials with the ability to self-heal and recover their structural integrity offer many advantages for applications in biomedicine. The past decade has witnessed the rapid emergence of a new class of self-healing biomaterials commonly termed injectable, or printable in the context of 3D printing. These self-healing injectable biomaterials, mostly hydrogels and other soft condensed matter based on reversible chemistry, are able to temporarily fluidize under shear stress and subsequently recover their original mechanical properties. Self-healing injectable hydrogels offer distinct advantages compared to traditional biomaterials. Most notably, they can be administered in a locally targeted and minimally invasive manner through a narrow syringe without the need for invasive surgery.

Their moldability allows for a patient-specific intervention and shows great prospects for personalized medicine. Injected hydrogels can facilitate tissue regeneration in multiple ways owing to their viscoelastic and diffusive nature, ranging from simple mechanical support, spatiotemporally controlled delivery of cells or therapeutics, to local recruitment and modulation of host cells to promote tissue regeneration. Consequently, self-healing injectable hydrogels have been at the forefront of many cutting-edge tissue regeneration strategies. This study provides a critical review of the current state of self-healing injectable hydrogels for tissue regeneration. As key challenges toward further maturation of this exciting research field, we identify (i) the trade-off between the self-healing and injectability of hydrogels vs their physical stability, (ii) the lack of consensus on rheological characterization and quantitative benchmarks for self-healing injectable hydrogels, particularly regarding the capillary flow in syringes, and (iii) practical limitations regarding translation toward therapeutically effective formulations for regeneration of specific tissues. Hence, here we (i) review chemical and physical design strategies for self-healing injectable hydrogels, (ii) provide a practical guide for their rheological analysis, and (iii) showcase their applicability for regeneration of various tissues and 3D printing of complex tissues and organoids.

Potential advantages of self-healing injectable hydrogels
for tissue regeneration

Minimally invasive administration through narrow syringes

Moldability to patient-specific irrgular tissue defects

High spatial control of hydrogels without off-target leakage

Spatiotemorally controlled delivery of cells and therapeutics

Increased cell survival and function compared to suspension-based delivery

Suitability as 3D (bio)printing inks and support baths in freeform 3D printing

Biomaterials are designed to support, treat, augment, repair, or replace a part of body tissue or its function. Over the past decades, the steady rise and optimization of biomaterials has revolutionized many fields of medicine. (1,2) Biomaterials are subjected to continuous mechanical load or biochemical degradation which can impair their structural integrity and ultimately their functionality. Hence, extensive research efforts have been dedicated to the design of biomaterials that are self-healing, i.e., can halt or even reverse damages induced by mechanical or biochemical stresses. While self-healing may refer to the recovery of any biomaterial function, it most commonly describes the recovery of a material’s structural integrity and associated mechanical properties. (3-8) This review provides an overview of self-healing injectable hydrogels, a particular class of self-healing biomaterials that can fluidize under shear stress followed by recovery of their mechanical properties, and show exciting prospects for applications in tissue regeneration and 3D (bio)printing.

In context of self-healing, hydrogels are a promising class of biomaterials because of their dynamic and diffusive nature compared to traditional polymers, ceramics, or cements. Hydrogels with self-healing capacity can be assembled from a large toolbox of biocompatible materials exploiting noncovalent or dynamic covalent interactions. (9-13) Hydrogels have long been recognized as promising biomaterial platforms with various applications in biomedicine. (14-16) Hydrogels can be engineered to closely resemble the natural 3D environment, distribution of cell ligands and nutrients, and viscoelasticity of the extracellular matrix (ECM) of various tissues. (17-19) They are common scaffold materials for the ex situ cultivation of tissue or organoids, commonly known as tissue engineering. (20-22) Hydrogels are also increasingly used in cell culture, particularly in 3D, which has resolved many issues such as abnormal cell shaping or differentiation observed for cells cultured in 2D monolayers or on hard substrates. (23-25) Hydrogel-based cell culture is still in its infancy, and several groups have provided practical guides on the use of hydrogels for cell culture to promote its implementation in biomedical research. (26-29)

One particularly interesting class of self-healing hydrogels involves injectable or printable (in context of 3D printing) hydrogels. These self-healing injectable hydrogels are able to temporarily fluidize under shear stress and recover their original structure and mechanical properties after release of the applied stress, as schematically illustrated in Figure 1. This unique feature of self-healing injectable hydrogels has paved the way for several exciting applications in biomedicine, as summarized in Box 1. Most importantly, self-healing injectable hydrogels can be administered in a minimally invasive manner at the target site. (32,33) The hydrogels can be structurally and mechanically fine-tuned to mimic various tissues and aid regeneration by providing mechanical tissue support. (33,34) Because of their rapid self-healing, these hydrogels can be administered with high spatial control and mold into patient-specific tissue defects without undesired off-target leakage. This opens many avenues for personalized interventions, in particular in combination with noninvasive imaging technqiues. (35-38) Self-healing injectable hydrogels can be exploited for locally targeted and sustained delivery of therapeutics, (39-42) and their shear-thinning plug flow in syringes facilitates administration of live cells. (43-45) Ultimately, self-healing injectable hydrogels are increasingly used as inks in 3D (bio)printing or support matrices in freeform 3D printing, and facilitate printing of complex tissue models and organoids with spatial control over material composition and distribution of cells or biomolecules. (46-49)

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Self-Healing Injectable Hydrogels for Tissue Regeneration, Pascal Bertsch, Mani Diba, David J. Mooney, and Sander C. G. Leeuwenburgh, Chemical Reviews
DOI: 10.1021/acs.chemrev.2c00179

excipients formulation

Self-Healing Injectable Hydrogels for Tissue Regeneration

Potential advantages of self-healing injectable hydrogels for tissue regeneration

Potential advantages of self-healing injectable hydrogels
for tissue regeneration